Objectives To determine if a specific intervention reduces the composite of progression of patien... more Objectives To determine if a specific intervention reduces the composite of progression of patients with COVID-19-related disease to organ failure or death as measured by time to incidence of any one of the following: death, invasive mechanical ventilation, ECMO, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). Trial design Randomised, parallel arm, open-label, adaptive platform Phase 2/3 trial of potential disease modifying therapies in patients with late stage 1/stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical, laboratory and radiological assessment. Participants Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a risk count (as defined below) >3 OR ≥3 if risk count includes “Radiographic severity score >3”. A ...
Objectives To determine if a specific immunomodulatory intervention reduces progression of COVID-... more Objectives To determine if a specific immunomodulatory intervention reduces progression of COVID-19-related disease to organ failure or death, compared to standard of care (SoC). Trial design Randomised, parallel 3-arm (1:1:1 ratio), open-label, Phase IV platform trial of immunomodulatory therapies in patients with late stage 1 or stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical and/or radiological assessment. Participants Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a Risk count (as defined below) >3 OR ≥3 if risk count includes “Radiographic severity score >3”. A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >...
Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1... more Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 u...
1205 activity states [remission (SLEDAI-2K=0) and lupus low disease activity state (LL-DAS)], acc... more 1205 activity states [remission (SLEDAI-2K=0) and lupus low disease activity state (LL-DAS)], accrual of irreversible damage (SLICC damage index, SDI), number and severity of flares, and side-effects. Analyses were performed at quarterly intervals and only patients with at least 3 months of follow-up were included in the study. Results: A total of 56 patients were included [53 women (94.6%), mean (SD) age 46.3 (12.7) years]. Evidence of serologic activity (low C3/C4 and/or high anti-ds DNA) was evident in 30 patients (53.5%). Most frequent manifestations were arthritis (82.1%), inflammatory rash (73.2%), active hair loss (57.1%), mucosal ulcers (26.8%) and leukopenia (10.7%). Median (range) duration of follow-up was 9.1 (2.9-34.6) months. We observed a significant decrease in the SLEDAI-2K, physician global assessment (PGA) and daily prednisone dose over time, starting as early as 3 months after belimumab initiation (Table 1). This effect was significantly more pronounced in patients who were serologically active (SA) at baseline, even after exclusion of the serologic component of the SLEDAI [median (range) clinical SLEDAI-2K for SA patients: 7 (1-24) at baseline vs. 2 (0-16) at 6 months and 2 (0-16) at 12 months, p<0.0001 and p=0.013, respectively; for serologically inactive patients: 6 (2-23) at baseline vs. 6 (0-14) at 6 months and 5 (0-18) at 12 months, p=0.017 and p=0.024, respectively]. For patients with ≥12 months of follow-up (n=20), belimumab treatment resulted in a significant decrease in flare rate [median (range) total number of flares for the 12 months before and after belimumab treatment, 3 (0-7) and 0 (0-2), respectively, p<0.0001). 10 patients (17.8%) discontinued belimumab due to inefficacy after a median (range) 7.1 (5.5-20.4) months of therapy and 5 patients discontinued due to planned pregnancy. There were no drug discontinuations due to side-effects. Conclusions: In real-life clinical settings, belimumab is efficacious in controlling disease activity of SLE and permitting tapering of glucocorticoid dose. Similar to data from RCTs, this effect seems to be more pronounced in serologically active patients.
We investigated whether rituximab, an anti-B-cell therapy, improved symptoms of fatigue and oral ... more We investigated whether rituximab, an anti-B-cell therapy, improved symptoms of fatigue and oral dryness in patients with Primary Sjögren's Syndrome (PSS). Multicentre, randomised, double-blind, parallel-group placebo-controlled trial, including Health Economic Analysis. Anti-Ro positive patients with PSS, symptomatic fatigue and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally-randomised to either placebo IV or rituximab IV (1000mg in 250mL) at weeks 0, 2, 24 and 26, with pre-and post-infusion medication including corticosteroids. Primary endpoint was the proportion of patients achieving 30% reduction in either fatigue or oral dryness at 48 weeks, measured by Visual Analogue Scale. Other outcomes included salivary and lachrymal flow rates, quality of life, ESSDAI and ESSPRI, symptoms of ocular and overall dryness, pain, global disease assessment and cost-effectiveness. ISRCTN 65360827 Results: All patients (n=...
The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled tria... more The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 1...
Wan-Fai (2016) Fatigue in primary Sjögren's syndrome is associated with lower levels of proinflam... more Wan-Fai (2016) Fatigue in primary Sjögren's syndrome is associated with lower levels of proinflammatory cytokines. RMD Open, 2 (2). e000282.
Chaperonins have classically been thought of as intracellular molecules involved in the correct f... more Chaperonins have classically been thought of as intracellular molecules involved in the correct folding of proteins. Their expression is upregulated during times of stress such as heat (hence their common nomenclature as heat shock proteins [HSP]), anoxia, hypoglycaemia and reactive oxygen species [1]. These are conditions found in infected tissues or in tissues with chronic inflammation such as the rheumatoid synovium. In their intracellular location they protect the cell from apoptotic death due to stress. Increasingly chaperonins have been recognised to subserve extracellular functions for which they have received the name 'chaperokines' since they bind to specific receptors on the cell surface and activate cells of the innate immune system to secrete inflammatory cytokines, chemokines and small molecular weight mediators such as prostaglandins [2]. Indeed, an early event in inflammation is cell stress/necrosis leading to the release of HSP60 and HSP70 that binds via a CD14-mediated mechanism to Toll-like receptors 2 and 4 [2] as part of the 'danger' signal [3]. The secretion of tumour necrosis factor alpha, IL-1, IL-12 and other chemokines prepares the environment for a TH1 adaptive immune response. It is now recognised that some chaperonins, such as BiP and HSP27, may activate the innate immune system to secrete anti-inflammatory cytokines, such as IL-10 [4,5] that may skew the adaptive immune response to TH2. Recent work by our group has shown that BiP can not only prevent but also treat ongoing collagen-induced arthritis in DBA/1 mice [6], suggesting that chaperonins may down modulate ongoing TH1 responses. Thus, it may be possible to suppress rheumatoid inflammation by administration of appropriate chaperonins such as BiP. Finally, chaperonins may be important system regulators determining the outcome between TH1 and Th2 immune responses. References 1. Pockley AG: Heat shock proteins as regulators of the immune response. Lancet 2003, 362:469-476. 2. Asea A: Chaperokine-induced signal transduction pathways. Exerc Immunol Rev 2003, 9:25-33. 3. Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301-305. 4. De AK, Kodys KM, Yeh BS, Miller-Graziano C: Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heatshock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus.
Genetic susceptibility to rheumatoid arthritis (RA), a common autoimmune disease, is associated w... more Genetic susceptibility to rheumatoid arthritis (RA), a common autoimmune disease, is associated with certain HLA-DR4 alleles. Treatments are rarely curative and are often tied to major side effects. We describe the development of a humanized mouse model wherein new, less toxic, vaccine-like treatments for RA might be pretested. This model includes four separate transgenes: HLA-DR*0401 and human CD4 molecules, a RA-related human autoantigenic protein (HCgp-39), and a T-cell receptor (TCRalphabeta) transgene specific for an important HCgp-39 epitope, eliciting strong Th1 responses in the context of HLA-DR*0401.
those children reporting joint or muscle pain during the past year. This approach may not have id... more those children reporting joint or muscle pain during the past year. This approach may not have identified children with quiescent or very mild joint symptoms. This study provides new and important information on the prevalence of musculoskeletal symptoms and inflammatory arthropathy in children with IBD. The data have been collected from one of the largest paediatric (secondary and tertiary) IBD cohorts in the UK. Inflammatory arthropathy is uncommon in children with IBD and a prospective longitudinal study is indicated to accurately determine the incidence and pattern of inflammatory arthritis in children with IBD over time. The results of this study are reassuring and of relevance to both general and specialist paediatricians looking after children with IBD. This study highlights the need for all physicians involved in the care of children with IBD to examine the musculoskeletal system at every available opportunity.
This review examines the field of current HLA class II transgenic mouse models and the individual... more This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA-DR4 transgenic lines with normally expressed HLA-DR4 molecules have been produced. To obtain adequate positive selection of the HLA-DR4-restricted CD4+ T-cell repertoire in these mice it is essential both to introduce a human CD4 transgene, and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA-DR4 transgenic mice have been used to determine the immunogenic CD4+ T-cell epitopes of several human autoantigenic proteins.
Objective. To analyze the CD4؉ ؉ ؉ T cell responses to the human cartilage antigen glycoprotein-3... more Objective. To analyze the CD4؉ ؉ ؉ T cell responses to the human cartilage antigen glycoprotein-39 (HCgp-39) in the context of rheumatoid arthritis (RA)-associated (DR␣1*0401) and nonassociated (DR␣1*0402) HLA class II molecules. Methods. Large numbers of HCgp-39-specific T cell hybridomas were generated following immunization of HLA-DR4/human CD4 transgenic, murine major histocompatibility complex class II deficient mice with native HCgp-39. Fine epitope mapping of DR␣1*0401and DR␣1*0402-restricted T cell hybridomas was performed using overlapping synthetic peptides. Antigenspecific cytokine production by lymph node T cells was evaluated after immunization with native antigen. Proliferative T cell responses of healthy human subjects were compared with the T cell responses of patients with active RA using HCgp-39 epitopes defined in HLA-DR4 transgenic mice. Results. CD4؉ ؉ ؉ T cells from DR␣1*0401 and DR␣1*0402 transgenic mice identified completely different immunodominant peptide epitopes of HCgp-39, and this was not explained by known DR4-binding motifs or direct peptide-binding studies. DR␣1*0401restricted, antigen-specific T cells produced significantly more interferon-␥ and tumor necrosis factor ␣ in response to HCgp-39 than did T cells from DR␣1*0402 transgenic mice. Finally, HCgp-39 peptides defined in DR␣1*0401 transgenic mice stimulated T cells from HLA-DR4 positive human subjects and RA patients, but not T cells from HLA-DR4 negative individuals. Conclusion. T cell epitopes of HCgp-39 that were defined in HLA-DR4 transgenic mice stimulated T cells from human subjects carrying RA-associated HLA-DR4 alleles. HLA-DR4 molecules may influence the disease process in RA both by presentation of selected peptide epitopes and by promoting the production of proinflammatory cytokines in synovial joints. Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints that affects ϳ1% of the Caucasian population (1). Although the pathogenesis of RA is multifactorial, the major histocompatibility complex (MHC) in humans accounts for one-third to one-half of the total genetic contribution to disease susceptibility (2). A consensus motif encoded by the third hypervariable region of the HLA-DRB1 sequence of RA-associated alleles (DRB1*0401, *0404, *0405, *0408, and *0101) has been identified as one of the critical genetic elements of RA susceptibility (3-6), and the baseline frequency of expression of this diseaselinked "shared epitope" motif correlates very closely with the prevalence of RA in a given population (7). RA patients carrying 2 copies of disease-associated HLA-DRB1 alleles may have both an earlier disease onset and more severe erosive disease (8). Despite these strong
technique. An excess of antibodies can result in diffuse or faint staining. 10 To confirm this hy... more technique. An excess of antibodies can result in diffuse or faint staining. 10 To confirm this hypothesis, some of the anti-CCP positive sera, usually diluted 1:20 for AKA determination, were then diluted in phosphate-buffered saline up to 1:200. Patients 6, 7 and 10 then showed the characteristic linear laminated pattern. These patients who were first considered to be AKA negative were in fact AKA positive! To conclude, testing for autoantibodies is highly relevant in the diagnosis or exclusion of many systemic autoimmune diseases, including RA. Our data show that IIF is an interesting diagnostic tool, provided the biologist has trained staff, quality controls, proficiency testing and keeps in mind the possible occurrence of prozone effects. As much as possible, AKA and anti-CCP antibodies should always be combined for optimum diagnostic performance. Solid-phase assays, which may be too expensive in some countries, can detect only anti-CCP antibodies, whereas IIF could give extra information such as the presence of antinuclear antibodies when examining for AKA.
T lymphocytes have been implicated in the pathogenesis of inflammatory arthritis for approximatel... more T lymphocytes have been implicated in the pathogenesis of inflammatory arthritis for approximately 30 years. Over that period a vast literature has described the phenotype, location and behaviour of T cells derived from patients with inflammatory rheumatological disease. The arthritiogenic roles of MHC class I and class II molecules, which present antigen to T cells, have been hotly debated. The
To explore the cytokine responses associated with T cell epitopes from human cartilage glycoprote... more To explore the cytokine responses associated with T cell epitopes from human cartilage glycoprotein 39 (HC gp-39) and the potential for modifying cytokine secretion using altered peptide ligands (APLs).
QJM: monthly journal of the Association of Physicians
Eosinophilic myositis is a rare entity accompanying parasitic infection or other inflammatory dis... more Eosinophilic myositis is a rare entity accompanying parasitic infection or other inflammatory disorders. Two cases are reported in which myalgia and eosinophilic infiltration of muscle occurred in the absence of associated disease, and twelve previously published cases of idiopathic eosinophilic myositis are reviewed. A classification system for idiopathic eosinophilic muscle disease is proposed, describing three distinct groups. Comparisons are drawn between these and other causes of eosinophilic muscle disease, outlining the differential diagnoses for each group.
Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is respon... more Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is responsible for much of the pain and disability experienced by patients with SSc. However, there is a limited evidence base to guide clinicians in the management of SSc-related digital vasculopathy. Our aim was to produce recommendations that would be helpful for clinicians, especially for those managing patients outside specialist centres. The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including digital vasculopathy. This overview presents the background and best practice consensus pathways for SSc-related RP, digital ulceration and critical ischaemia. Examples of drug therapies, including doses, are suggested in order to inform prescribing practice. A number of treatment algorithms are provided that are intended to provide the clinician with accessible reference tool...
Objectives To determine if a specific intervention reduces the composite of progression of patien... more Objectives To determine if a specific intervention reduces the composite of progression of patients with COVID-19-related disease to organ failure or death as measured by time to incidence of any one of the following: death, invasive mechanical ventilation, ECMO, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). Trial design Randomised, parallel arm, open-label, adaptive platform Phase 2/3 trial of potential disease modifying therapies in patients with late stage 1/stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical, laboratory and radiological assessment. Participants Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a risk count (as defined below) >3 OR ≥3 if risk count includes “Radiographic severity score >3”. A ...
Objectives To determine if a specific immunomodulatory intervention reduces progression of COVID-... more Objectives To determine if a specific immunomodulatory intervention reduces progression of COVID-19-related disease to organ failure or death, compared to standard of care (SoC). Trial design Randomised, parallel 3-arm (1:1:1 ratio), open-label, Phase IV platform trial of immunomodulatory therapies in patients with late stage 1 or stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical and/or radiological assessment. Participants Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a Risk count (as defined below) >3 OR ≥3 if risk count includes “Radiographic severity score >3”. A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >...
Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1... more Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 u...
1205 activity states [remission (SLEDAI-2K=0) and lupus low disease activity state (LL-DAS)], acc... more 1205 activity states [remission (SLEDAI-2K=0) and lupus low disease activity state (LL-DAS)], accrual of irreversible damage (SLICC damage index, SDI), number and severity of flares, and side-effects. Analyses were performed at quarterly intervals and only patients with at least 3 months of follow-up were included in the study. Results: A total of 56 patients were included [53 women (94.6%), mean (SD) age 46.3 (12.7) years]. Evidence of serologic activity (low C3/C4 and/or high anti-ds DNA) was evident in 30 patients (53.5%). Most frequent manifestations were arthritis (82.1%), inflammatory rash (73.2%), active hair loss (57.1%), mucosal ulcers (26.8%) and leukopenia (10.7%). Median (range) duration of follow-up was 9.1 (2.9-34.6) months. We observed a significant decrease in the SLEDAI-2K, physician global assessment (PGA) and daily prednisone dose over time, starting as early as 3 months after belimumab initiation (Table 1). This effect was significantly more pronounced in patients who were serologically active (SA) at baseline, even after exclusion of the serologic component of the SLEDAI [median (range) clinical SLEDAI-2K for SA patients: 7 (1-24) at baseline vs. 2 (0-16) at 6 months and 2 (0-16) at 12 months, p<0.0001 and p=0.013, respectively; for serologically inactive patients: 6 (2-23) at baseline vs. 6 (0-14) at 6 months and 5 (0-18) at 12 months, p=0.017 and p=0.024, respectively]. For patients with ≥12 months of follow-up (n=20), belimumab treatment resulted in a significant decrease in flare rate [median (range) total number of flares for the 12 months before and after belimumab treatment, 3 (0-7) and 0 (0-2), respectively, p<0.0001). 10 patients (17.8%) discontinued belimumab due to inefficacy after a median (range) 7.1 (5.5-20.4) months of therapy and 5 patients discontinued due to planned pregnancy. There were no drug discontinuations due to side-effects. Conclusions: In real-life clinical settings, belimumab is efficacious in controlling disease activity of SLE and permitting tapering of glucocorticoid dose. Similar to data from RCTs, this effect seems to be more pronounced in serologically active patients.
We investigated whether rituximab, an anti-B-cell therapy, improved symptoms of fatigue and oral ... more We investigated whether rituximab, an anti-B-cell therapy, improved symptoms of fatigue and oral dryness in patients with Primary Sjögren's Syndrome (PSS). Multicentre, randomised, double-blind, parallel-group placebo-controlled trial, including Health Economic Analysis. Anti-Ro positive patients with PSS, symptomatic fatigue and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally-randomised to either placebo IV or rituximab IV (1000mg in 250mL) at weeks 0, 2, 24 and 26, with pre-and post-infusion medication including corticosteroids. Primary endpoint was the proportion of patients achieving 30% reduction in either fatigue or oral dryness at 48 weeks, measured by Visual Analogue Scale. Other outcomes included salivary and lachrymal flow rates, quality of life, ESSDAI and ESSPRI, symptoms of ocular and overall dryness, pain, global disease assessment and cost-effectiveness. ISRCTN 65360827 Results: All patients (n=...
The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled tria... more The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 1...
Wan-Fai (2016) Fatigue in primary Sjögren's syndrome is associated with lower levels of proinflam... more Wan-Fai (2016) Fatigue in primary Sjögren's syndrome is associated with lower levels of proinflammatory cytokines. RMD Open, 2 (2). e000282.
Chaperonins have classically been thought of as intracellular molecules involved in the correct f... more Chaperonins have classically been thought of as intracellular molecules involved in the correct folding of proteins. Their expression is upregulated during times of stress such as heat (hence their common nomenclature as heat shock proteins [HSP]), anoxia, hypoglycaemia and reactive oxygen species [1]. These are conditions found in infected tissues or in tissues with chronic inflammation such as the rheumatoid synovium. In their intracellular location they protect the cell from apoptotic death due to stress. Increasingly chaperonins have been recognised to subserve extracellular functions for which they have received the name 'chaperokines' since they bind to specific receptors on the cell surface and activate cells of the innate immune system to secrete inflammatory cytokines, chemokines and small molecular weight mediators such as prostaglandins [2]. Indeed, an early event in inflammation is cell stress/necrosis leading to the release of HSP60 and HSP70 that binds via a CD14-mediated mechanism to Toll-like receptors 2 and 4 [2] as part of the 'danger' signal [3]. The secretion of tumour necrosis factor alpha, IL-1, IL-12 and other chemokines prepares the environment for a TH1 adaptive immune response. It is now recognised that some chaperonins, such as BiP and HSP27, may activate the innate immune system to secrete anti-inflammatory cytokines, such as IL-10 [4,5] that may skew the adaptive immune response to TH2. Recent work by our group has shown that BiP can not only prevent but also treat ongoing collagen-induced arthritis in DBA/1 mice [6], suggesting that chaperonins may down modulate ongoing TH1 responses. Thus, it may be possible to suppress rheumatoid inflammation by administration of appropriate chaperonins such as BiP. Finally, chaperonins may be important system regulators determining the outcome between TH1 and Th2 immune responses. References 1. Pockley AG: Heat shock proteins as regulators of the immune response. Lancet 2003, 362:469-476. 2. Asea A: Chaperokine-induced signal transduction pathways. Exerc Immunol Rev 2003, 9:25-33. 3. Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301-305. 4. De AK, Kodys KM, Yeh BS, Miller-Graziano C: Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heatshock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus.
Genetic susceptibility to rheumatoid arthritis (RA), a common autoimmune disease, is associated w... more Genetic susceptibility to rheumatoid arthritis (RA), a common autoimmune disease, is associated with certain HLA-DR4 alleles. Treatments are rarely curative and are often tied to major side effects. We describe the development of a humanized mouse model wherein new, less toxic, vaccine-like treatments for RA might be pretested. This model includes four separate transgenes: HLA-DR*0401 and human CD4 molecules, a RA-related human autoantigenic protein (HCgp-39), and a T-cell receptor (TCRalphabeta) transgene specific for an important HCgp-39 epitope, eliciting strong Th1 responses in the context of HLA-DR*0401.
those children reporting joint or muscle pain during the past year. This approach may not have id... more those children reporting joint or muscle pain during the past year. This approach may not have identified children with quiescent or very mild joint symptoms. This study provides new and important information on the prevalence of musculoskeletal symptoms and inflammatory arthropathy in children with IBD. The data have been collected from one of the largest paediatric (secondary and tertiary) IBD cohorts in the UK. Inflammatory arthropathy is uncommon in children with IBD and a prospective longitudinal study is indicated to accurately determine the incidence and pattern of inflammatory arthritis in children with IBD over time. The results of this study are reassuring and of relevance to both general and specialist paediatricians looking after children with IBD. This study highlights the need for all physicians involved in the care of children with IBD to examine the musculoskeletal system at every available opportunity.
This review examines the field of current HLA class II transgenic mouse models and the individual... more This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA-DR4 transgenic lines with normally expressed HLA-DR4 molecules have been produced. To obtain adequate positive selection of the HLA-DR4-restricted CD4+ T-cell repertoire in these mice it is essential both to introduce a human CD4 transgene, and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA-DR4 transgenic mice have been used to determine the immunogenic CD4+ T-cell epitopes of several human autoantigenic proteins.
Objective. To analyze the CD4؉ ؉ ؉ T cell responses to the human cartilage antigen glycoprotein-3... more Objective. To analyze the CD4؉ ؉ ؉ T cell responses to the human cartilage antigen glycoprotein-39 (HCgp-39) in the context of rheumatoid arthritis (RA)-associated (DR␣1*0401) and nonassociated (DR␣1*0402) HLA class II molecules. Methods. Large numbers of HCgp-39-specific T cell hybridomas were generated following immunization of HLA-DR4/human CD4 transgenic, murine major histocompatibility complex class II deficient mice with native HCgp-39. Fine epitope mapping of DR␣1*0401and DR␣1*0402-restricted T cell hybridomas was performed using overlapping synthetic peptides. Antigenspecific cytokine production by lymph node T cells was evaluated after immunization with native antigen. Proliferative T cell responses of healthy human subjects were compared with the T cell responses of patients with active RA using HCgp-39 epitopes defined in HLA-DR4 transgenic mice. Results. CD4؉ ؉ ؉ T cells from DR␣1*0401 and DR␣1*0402 transgenic mice identified completely different immunodominant peptide epitopes of HCgp-39, and this was not explained by known DR4-binding motifs or direct peptide-binding studies. DR␣1*0401restricted, antigen-specific T cells produced significantly more interferon-␥ and tumor necrosis factor ␣ in response to HCgp-39 than did T cells from DR␣1*0402 transgenic mice. Finally, HCgp-39 peptides defined in DR␣1*0401 transgenic mice stimulated T cells from HLA-DR4 positive human subjects and RA patients, but not T cells from HLA-DR4 negative individuals. Conclusion. T cell epitopes of HCgp-39 that were defined in HLA-DR4 transgenic mice stimulated T cells from human subjects carrying RA-associated HLA-DR4 alleles. HLA-DR4 molecules may influence the disease process in RA both by presentation of selected peptide epitopes and by promoting the production of proinflammatory cytokines in synovial joints. Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints that affects ϳ1% of the Caucasian population (1). Although the pathogenesis of RA is multifactorial, the major histocompatibility complex (MHC) in humans accounts for one-third to one-half of the total genetic contribution to disease susceptibility (2). A consensus motif encoded by the third hypervariable region of the HLA-DRB1 sequence of RA-associated alleles (DRB1*0401, *0404, *0405, *0408, and *0101) has been identified as one of the critical genetic elements of RA susceptibility (3-6), and the baseline frequency of expression of this diseaselinked "shared epitope" motif correlates very closely with the prevalence of RA in a given population (7). RA patients carrying 2 copies of disease-associated HLA-DRB1 alleles may have both an earlier disease onset and more severe erosive disease (8). Despite these strong
technique. An excess of antibodies can result in diffuse or faint staining. 10 To confirm this hy... more technique. An excess of antibodies can result in diffuse or faint staining. 10 To confirm this hypothesis, some of the anti-CCP positive sera, usually diluted 1:20 for AKA determination, were then diluted in phosphate-buffered saline up to 1:200. Patients 6, 7 and 10 then showed the characteristic linear laminated pattern. These patients who were first considered to be AKA negative were in fact AKA positive! To conclude, testing for autoantibodies is highly relevant in the diagnosis or exclusion of many systemic autoimmune diseases, including RA. Our data show that IIF is an interesting diagnostic tool, provided the biologist has trained staff, quality controls, proficiency testing and keeps in mind the possible occurrence of prozone effects. As much as possible, AKA and anti-CCP antibodies should always be combined for optimum diagnostic performance. Solid-phase assays, which may be too expensive in some countries, can detect only anti-CCP antibodies, whereas IIF could give extra information such as the presence of antinuclear antibodies when examining for AKA.
T lymphocytes have been implicated in the pathogenesis of inflammatory arthritis for approximatel... more T lymphocytes have been implicated in the pathogenesis of inflammatory arthritis for approximately 30 years. Over that period a vast literature has described the phenotype, location and behaviour of T cells derived from patients with inflammatory rheumatological disease. The arthritiogenic roles of MHC class I and class II molecules, which present antigen to T cells, have been hotly debated. The
To explore the cytokine responses associated with T cell epitopes from human cartilage glycoprote... more To explore the cytokine responses associated with T cell epitopes from human cartilage glycoprotein 39 (HC gp-39) and the potential for modifying cytokine secretion using altered peptide ligands (APLs).
QJM: monthly journal of the Association of Physicians
Eosinophilic myositis is a rare entity accompanying parasitic infection or other inflammatory dis... more Eosinophilic myositis is a rare entity accompanying parasitic infection or other inflammatory disorders. Two cases are reported in which myalgia and eosinophilic infiltration of muscle occurred in the absence of associated disease, and twelve previously published cases of idiopathic eosinophilic myositis are reviewed. A classification system for idiopathic eosinophilic muscle disease is proposed, describing three distinct groups. Comparisons are drawn between these and other causes of eosinophilic muscle disease, outlining the differential diagnoses for each group.
Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is respon... more Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is responsible for much of the pain and disability experienced by patients with SSc. However, there is a limited evidence base to guide clinicians in the management of SSc-related digital vasculopathy. Our aim was to produce recommendations that would be helpful for clinicians, especially for those managing patients outside specialist centres. The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including digital vasculopathy. This overview presents the background and best practice consensus pathways for SSc-related RP, digital ulceration and critical ischaemia. Examples of drug therapies, including doses, are suggested in order to inform prescribing practice. A number of treatment algorithms are provided that are intended to provide the clinician with accessible reference tool...
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Papers by Frances Hall