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Papers by Paul Eggleton

International Journal of Rheumatic Diseases, 2015

Patients with rheumatoid arthritis (RA) and co-existent bronchiectasis (BRRA) have a five-fold in... more Patients with rheumatoid arthritis (RA) and co-existent bronchiectasis (BRRA) have a five-fold increased mortality compared to rheumatoid arthritis alone. Yet previous studies have found no difference in clinical and serological markers of RA disease severity between BRRA patients and RA alone. However, RA disease activity measures such as Disease Activity Score of 28 joints - C-reactive protein (DAS28-CRP) and anti-cyclic citrullinated peptide antibodies (anti-CCP) have not been studied, so we assessed these parameters in patients with BRRA and RA alone. BRRA patients (n = 53) had high-resolution computed tomography proven bronchiectasis without any interstitial lung disease and ≥ 2 respiratory infections/year. RA alone patients (n = 50) had no clinical or radiological evidence of lung disease. DAS28-CRP, rheumatoid factor (immunoglobulin M) and anti-CCP were measured in all patients, together with detailed clinical and radiology records. In BRRA, bronchiectasis predated RA in 58% of patients. BRRA patients had higher DAS28 scores (3.51 vs. 2.59), higher levels of anti-CCP (89% vs. 46%) and rheumatoid factor (79% vs. 52%) (P = 0.003) compared to RA alone. Where hand and foot radiology findings were recorded, 29/37 BRRA (78%) and 13/30 (43%) RA alone had evidence of erosive change (P = 0.003). There were no significant differences between groups in smoking history or disease-modifying anti-rheumatic drug/biologic therapy. Increased levels of RA disease activity, severity and RA autoantibodies are demonstrated in patients with RA and co-existent bronchiectasis compared to patients with RA alone, despite lower tobacco exposure. This study demonstrates that BRRA is a more severe systemic disease than RA alone.

Arthritis & rheumatology (Hoboken, N.J.), Jan 27, 2015

Objective Bronchiectasis (BR) is a risk factor for rheumatoid arthritis (RA). Here we examine the... more Objective Bronchiectasis (BR) is a risk factor for rheumatoid arthritis (RA). Here we examine the potential of BR in generating rheumatoid factors (RFs) and anti-citrullinated peptide antibodies (ACPA) in patients with BR alone and in patients with BR and RA (BRRA). Methods We studied 122 patients with BR alone, 50 BRRA, 50 RA without lung disease, with 87 asthma and 79 healthy subjects as controls. RFs were measured by an automated analyzer, and ACPA using CCP2. Fine specificities to citrullinated α-enolase (CEP-1), citrullinated vimentin (cVim) and fibrinogen (cFib) with their arginine control peptides (REP-1, Vim and Fib) measured by ELISA. Results In the BR patients 39% were ever smokers compared to 42% of the controls. Serum samples from BR patients had an increased frequency of RF (25%; p< 0.05) and 5% to CCP2, 7% to CEP-1, 7% to cVIM (all p=ns) and 12% cFib (p <0.05). There was also a corresponding increase in antibodies to the arginine-containing control peptides in th...

Chronic wounds, defined as wounds that fail to heal in the predictable order and time frame of ac... more Chronic wounds, defined as wounds that fail to heal in the predictable order and time frame of acute wounds, are a huge burden on health services and the economy throughout the world. In the United States, it is estimated that 3-6 million people suffer from one of three main types of chronic wound - diabetic, venous or pressure ulcers, and that the total cost of wound care in the USA is around $3 billion per year. The development of chronic wounds is complex and is a result of alterations in a number of physiological processes. Venous ulcers are the most common form of chronic wound, and occur as a result of faulty venous valves, leading to hypertension inside the crural veins and capillaries, and then oedema. Diabetic ulcer patients typically have damaged microcirculation and impaired immune function. Pressure ulcers arise from physical immobility leading to poor circulation. Common features of chronic wounds are ischemia, hypoxia and bacterial infection. Some diabetic patients wit...

Wound Repair and Regeneration

Hyperbaric oxygen (HBO) therapy is an effective treatment for diabetic chronic wounds. HBO reduce... more Hyperbaric oxygen (HBO) therapy is an effective treatment for diabetic chronic wounds. HBO reduces inflammation and accelerates wound healing, by mechanisms that remain unclear. Here we examined a mechanism by which HBO may reduce neutrophil recruitment, through changes in endothelial and neutrophil adhesion molecule expression and function. Human umbilical vein endothelial cells (HUVEC) and neutrophils were exposed to selected chronic wound conditions, comprising hypoxia in the presence of lipopolysaccharide and TNF-α, and then treated with HBO. We observed neutrophil adhesion to endothelial cells following treatment with chronic wound conditions, which was reversed by HBO treatment. This was partly explained by reduced expression of endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by HBO. No changes in neutrophil adhesion molecule expression (CD18, CD11b, CD62L, CD31) were observed following HBO treatment. However, HBO decreased hydrogen peroxide...

Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc

Hyperbaric oxygen has proven to be a useful treatment for chronic wounds. However, therapeutic co... more Hyperbaric oxygen has proven to be a useful treatment for chronic wounds. However, therapeutic conditions vary between treatment centers, and we wished to investigate the effects of different treatment pressures on cells under inflammatory conditions. Endothelial cells were exposed to a chronic wound model comprising hypoxia (2% O2 at 1 atmosphere absolute (atm abs); PO2 approximately 2 kPa) in the presence of 0.5 microg/ml lipopolysaccharide and 1 ng/ml TNF-alpha for 24 hours, then treated with normobaric oxygen (NBO2; 95%O2/5%CO2 at 1.0 atm abs; PO2 approximately 96.3 kPa), hyperbaric oxygen (HBO2) at 1.5 atm abs (1.5HBO2; 96.7%O2/3.3%CO2 at 1.5 atm abs; PO2 approximately 147 kPa), and HBO2 at 2.4 atm abs (2.4HBO2; 97.9%O2/2.1%CO2 at 2.4 atm abs; PO2 approximately 238 kPa). The mRNA expression of 92 inflammatory genes was then analyzed, and we identified changes in genes involved in adhesion molecule expression, angiogenesis and tissue remodeling, intracellular signaling, and cell...

Infection and immunity, 1997

To determine whether the lung surfactant proteins A (SP-A) and D (SP-D) are involved in the initi... more To determine whether the lung surfactant proteins A (SP-A) and D (SP-D) are involved in the initial protective immunity against opportunistic pulmonary fungal infections caused by Aspergillus fumigatus, we performed a series of in vitro functional studies to see if SP-A and SP-D enhanced binding, phagocytosis, activation, and killing of A. fumigatus conidia by human alveolar macrophages and circulating neutrophils. Both SP-A and SP-D bound to carbohydrate structures on A. fumigatus conidia in a calcium-dependent manner. SP-A and SP-D were also chemoattractant and significantly enhanced agglutination and binding of conidia to alveolar macrophages and neutrophils. Furthermore, in the presence of SP-A and SP-D, the phagocytosis, oxidative burst, and killing of A. fumigatus conidia by neutrophils were significantly increased. These findings indicate that SP-A and SP-D may have an important immunological role in the early antifungal defense responses in the lung, through inhibiting infec...

Journal of immunology (Baltimore, Md. : 1950), 1997

Two types of widely coexpressed, highly acidic, cell membrane binding proteins that display prefe... more Two types of widely coexpressed, highly acidic, cell membrane binding proteins that display preferential domain specificity for C1q have been described: a 60-kDa calreticulin homologue, designated cC1q-R, that binds to the collagen-like "stalk" and a 33-kDa glycoprotein with affinity for the globular "heads" (gC1q-R). Although the two molecules are known to be coexpressed on all cell types examined to date and often coelute during purification, there is no direct evidence showing that they associate with each other either on the membrane or when examined in a purified system. In this report we present the first evidence that 1) biotinylated cC1q-R binds to recombinant as well as native gC1q-R, as assessed by solid phase ELISA; 2) binding sites for cC1q-R are located within N-terminal residues 76 through 93 of the mature form of gC1q-R and within residues 204 through 218; 3) this interaction is inhibited by two mAbs, 60.11 and 46.23, that recognize primarily epito...

Annals of the Rheumatic Diseases, 2013

ABSTRACT Background Previous studies have found no difference in RA disease severity measures (ea... more ABSTRACT Background Previous studies have found no difference in RA disease severity measures (early morning stiffness, swollen joint count, HAQ, radiological findings) or auto-antibodies (rheumatoid factor) between patients with Bronchiectasis and Rheumatoid Arthritis (BRRA) and those with RA alone1,2. Current validated RA disease activity measures such as DAS28-CRP and modern autoantibodies, anti-cyclic citrullinated peptide antibodies (ACPA) have not been compared between these groups. Objectives To determine if there is a difference in RA disease activity/severity and autoantibody status between patients with Bronchiectasis and Rheumatoid Arthritis and those with RA alone. Methods Screening clinics at 3 NHS Trusts we identified 20 BRRA patients and 20 RA alone. BRRA patients had HRCT proven bronchiectasis without other lung disease and a history of ≥2 respiratory infections/year. RA patients had no respiratory symptoms, no respiratory disease and a normal CXR. All patients met the 2010 ACR/EULAR RA criteria. DAS28-CRP, serum RF(IgM) and ACPA(2nd generation assay) were measured in all patients. Current disease modifying drugs, biologic drugs and hand and foot x-ray findings were recorded from clinical record review. Results The groups were matched for RA disease duration, mean 12.9yrs BRRA group and 12.2yrs RA group. All components of DAS28-CRP except VAS were significantly higher in the BRRA group (Table 1). Autoantibody positivity in the BRRA group was significantly higher, 19 (95%) were positive for RF compared to 13 (65%) in the RA group (p=0.044) and 18 (90%) were positive for ACPA compared to 11 (55%) in the RA group (p=0.031). Where hand and foot x-rays were available, 9/15 BRRA (60%) and 6/15 (40%) RA had evidence of erosive change. There was no significant difference (p=0.75) in the proportion of patients on combination therapy with ≥ one disease modifying drug/biologic, 9/20 BRRA (45%) and 7/20 RA (35%). Conclusions Patients with BRRA have higher DAS28-CRP and autoantibody positivity than those with RA alone. All components of DAS28-CRP, except the VAS (global) were significantly higher in the BRRA group demonstrating that the increase does not simply reflect higher CRP secondary to recurrent respiratory infections. Although numbers were too small to prove significance, an increased proportion of BRRA patients had erosive radiological change. Despite these findings DMARD/Biologic treatment was no more aggressive in the BRRA group suggesting under treatment of RA. It is likely this reflects concerns DMARD/Biologic treatment may exacerbate respiratory infections. There is currently no consensus on how to treat this challenging patient group, further studies are urgently required. References . McMahon et al. Bronchiectasis and rheumatoid arthritis a clinical study. Ann Rheum Dis 1993;52:776-779. . Cortet et al. Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis 1997;56:596-600.

Background: Immunoassays measuring antibodies to synthetic cyclic citrullinated peptides (CCP) ca... more Background: Immunoassays measuring antibodies to synthetic cyclic citrullinated peptides (CCP) capture anti-citrullinated protein/peptide antibodies (ACPAs) with a spectrum of fine specificities including naturally occurring citrullinated auto antigens. It has recently been demonstrated that the pathogenic association between HLA-DRB1SE, PTPN22 and smoking is strongest for the RA subset that carry antibodies to native citrullinated peptides, a-enolase and vimentin. Furthermore, enhanced citrullinated peptide expression in lungs of smokers supports the hypothesis that autoimmunity in RA can be initiated during lung inflammation. The association between bronchiectasis (BR) and RA is well recognized, despite this the pathogenesis is unknown. We hypothesize that similar to smoking, lung inflammation/ infection in susceptible individuals with BR may result in the exposure of the native citrullinated peptides, development of autoantibodies and in selected patients initiate the autoimmunit...

International Journal of Rheumatic Diseases, 2015

Patients with rheumatoid arthritis (RA) and co-existent bronchiectasis (BRRA) have a five-fold in... more Patients with rheumatoid arthritis (RA) and co-existent bronchiectasis (BRRA) have a five-fold increased mortality compared to rheumatoid arthritis alone. Yet previous studies have found no difference in clinical and serological markers of RA disease severity between BRRA patients and RA alone. However, RA disease activity measures such as Disease Activity Score of 28 joints - C-reactive protein (DAS28-CRP) and anti-cyclic citrullinated peptide antibodies (anti-CCP) have not been studied, so we assessed these parameters in patients with BRRA and RA alone. BRRA patients (n = 53) had high-resolution computed tomography proven bronchiectasis without any interstitial lung disease and ≥ 2 respiratory infections/year. RA alone patients (n = 50) had no clinical or radiological evidence of lung disease. DAS28-CRP, rheumatoid factor (immunoglobulin M) and anti-CCP were measured in all patients, together with detailed clinical and radiology records. In BRRA, bronchiectasis predated RA in 58% of patients. BRRA patients had higher DAS28 scores (3.51 vs. 2.59), higher levels of anti-CCP (89% vs. 46%) and rheumatoid factor (79% vs. 52%) (P = 0.003) compared to RA alone. Where hand and foot radiology findings were recorded, 29/37 BRRA (78%) and 13/30 (43%) RA alone had evidence of erosive change (P = 0.003). There were no significant differences between groups in smoking history or disease-modifying anti-rheumatic drug/biologic therapy. Increased levels of RA disease activity, severity and RA autoantibodies are demonstrated in patients with RA and co-existent bronchiectasis compared to patients with RA alone, despite lower tobacco exposure. This study demonstrates that BRRA is a more severe systemic disease than RA alone.

Arthritis & rheumatology (Hoboken, N.J.), Jan 27, 2015

Objective Bronchiectasis (BR) is a risk factor for rheumatoid arthritis (RA). Here we examine the... more Objective Bronchiectasis (BR) is a risk factor for rheumatoid arthritis (RA). Here we examine the potential of BR in generating rheumatoid factors (RFs) and anti-citrullinated peptide antibodies (ACPA) in patients with BR alone and in patients with BR and RA (BRRA). Methods We studied 122 patients with BR alone, 50 BRRA, 50 RA without lung disease, with 87 asthma and 79 healthy subjects as controls. RFs were measured by an automated analyzer, and ACPA using CCP2. Fine specificities to citrullinated α-enolase (CEP-1), citrullinated vimentin (cVim) and fibrinogen (cFib) with their arginine control peptides (REP-1, Vim and Fib) measured by ELISA. Results In the BR patients 39% were ever smokers compared to 42% of the controls. Serum samples from BR patients had an increased frequency of RF (25%; p< 0.05) and 5% to CCP2, 7% to CEP-1, 7% to cVIM (all p=ns) and 12% cFib (p <0.05). There was also a corresponding increase in antibodies to the arginine-containing control peptides in th...

Chronic wounds, defined as wounds that fail to heal in the predictable order and time frame of ac... more Chronic wounds, defined as wounds that fail to heal in the predictable order and time frame of acute wounds, are a huge burden on health services and the economy throughout the world. In the United States, it is estimated that 3-6 million people suffer from one of three main types of chronic wound - diabetic, venous or pressure ulcers, and that the total cost of wound care in the USA is around $3 billion per year. The development of chronic wounds is complex and is a result of alterations in a number of physiological processes. Venous ulcers are the most common form of chronic wound, and occur as a result of faulty venous valves, leading to hypertension inside the crural veins and capillaries, and then oedema. Diabetic ulcer patients typically have damaged microcirculation and impaired immune function. Pressure ulcers arise from physical immobility leading to poor circulation. Common features of chronic wounds are ischemia, hypoxia and bacterial infection. Some diabetic patients wit...

Wound Repair and Regeneration

Hyperbaric oxygen (HBO) therapy is an effective treatment for diabetic chronic wounds. HBO reduce... more Hyperbaric oxygen (HBO) therapy is an effective treatment for diabetic chronic wounds. HBO reduces inflammation and accelerates wound healing, by mechanisms that remain unclear. Here we examined a mechanism by which HBO may reduce neutrophil recruitment, through changes in endothelial and neutrophil adhesion molecule expression and function. Human umbilical vein endothelial cells (HUVEC) and neutrophils were exposed to selected chronic wound conditions, comprising hypoxia in the presence of lipopolysaccharide and TNF-α, and then treated with HBO. We observed neutrophil adhesion to endothelial cells following treatment with chronic wound conditions, which was reversed by HBO treatment. This was partly explained by reduced expression of endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by HBO. No changes in neutrophil adhesion molecule expression (CD18, CD11b, CD62L, CD31) were observed following HBO treatment. However, HBO decreased hydrogen peroxide...

Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc

Hyperbaric oxygen has proven to be a useful treatment for chronic wounds. However, therapeutic co... more Hyperbaric oxygen has proven to be a useful treatment for chronic wounds. However, therapeutic conditions vary between treatment centers, and we wished to investigate the effects of different treatment pressures on cells under inflammatory conditions. Endothelial cells were exposed to a chronic wound model comprising hypoxia (2% O2 at 1 atmosphere absolute (atm abs); PO2 approximately 2 kPa) in the presence of 0.5 microg/ml lipopolysaccharide and 1 ng/ml TNF-alpha for 24 hours, then treated with normobaric oxygen (NBO2; 95%O2/5%CO2 at 1.0 atm abs; PO2 approximately 96.3 kPa), hyperbaric oxygen (HBO2) at 1.5 atm abs (1.5HBO2; 96.7%O2/3.3%CO2 at 1.5 atm abs; PO2 approximately 147 kPa), and HBO2 at 2.4 atm abs (2.4HBO2; 97.9%O2/2.1%CO2 at 2.4 atm abs; PO2 approximately 238 kPa). The mRNA expression of 92 inflammatory genes was then analyzed, and we identified changes in genes involved in adhesion molecule expression, angiogenesis and tissue remodeling, intracellular signaling, and cell...

Infection and immunity, 1997

To determine whether the lung surfactant proteins A (SP-A) and D (SP-D) are involved in the initi... more To determine whether the lung surfactant proteins A (SP-A) and D (SP-D) are involved in the initial protective immunity against opportunistic pulmonary fungal infections caused by Aspergillus fumigatus, we performed a series of in vitro functional studies to see if SP-A and SP-D enhanced binding, phagocytosis, activation, and killing of A. fumigatus conidia by human alveolar macrophages and circulating neutrophils. Both SP-A and SP-D bound to carbohydrate structures on A. fumigatus conidia in a calcium-dependent manner. SP-A and SP-D were also chemoattractant and significantly enhanced agglutination and binding of conidia to alveolar macrophages and neutrophils. Furthermore, in the presence of SP-A and SP-D, the phagocytosis, oxidative burst, and killing of A. fumigatus conidia by neutrophils were significantly increased. These findings indicate that SP-A and SP-D may have an important immunological role in the early antifungal defense responses in the lung, through inhibiting infec...

Journal of immunology (Baltimore, Md. : 1950), 1997

Two types of widely coexpressed, highly acidic, cell membrane binding proteins that display prefe... more Two types of widely coexpressed, highly acidic, cell membrane binding proteins that display preferential domain specificity for C1q have been described: a 60-kDa calreticulin homologue, designated cC1q-R, that binds to the collagen-like "stalk" and a 33-kDa glycoprotein with affinity for the globular "heads" (gC1q-R). Although the two molecules are known to be coexpressed on all cell types examined to date and often coelute during purification, there is no direct evidence showing that they associate with each other either on the membrane or when examined in a purified system. In this report we present the first evidence that 1) biotinylated cC1q-R binds to recombinant as well as native gC1q-R, as assessed by solid phase ELISA; 2) binding sites for cC1q-R are located within N-terminal residues 76 through 93 of the mature form of gC1q-R and within residues 204 through 218; 3) this interaction is inhibited by two mAbs, 60.11 and 46.23, that recognize primarily epito...

Annals of the Rheumatic Diseases, 2013

ABSTRACT Background Previous studies have found no difference in RA disease severity measures (ea... more ABSTRACT Background Previous studies have found no difference in RA disease severity measures (early morning stiffness, swollen joint count, HAQ, radiological findings) or auto-antibodies (rheumatoid factor) between patients with Bronchiectasis and Rheumatoid Arthritis (BRRA) and those with RA alone1,2. Current validated RA disease activity measures such as DAS28-CRP and modern autoantibodies, anti-cyclic citrullinated peptide antibodies (ACPA) have not been compared between these groups. Objectives To determine if there is a difference in RA disease activity/severity and autoantibody status between patients with Bronchiectasis and Rheumatoid Arthritis and those with RA alone. Methods Screening clinics at 3 NHS Trusts we identified 20 BRRA patients and 20 RA alone. BRRA patients had HRCT proven bronchiectasis without other lung disease and a history of ≥2 respiratory infections/year. RA patients had no respiratory symptoms, no respiratory disease and a normal CXR. All patients met the 2010 ACR/EULAR RA criteria. DAS28-CRP, serum RF(IgM) and ACPA(2nd generation assay) were measured in all patients. Current disease modifying drugs, biologic drugs and hand and foot x-ray findings were recorded from clinical record review. Results The groups were matched for RA disease duration, mean 12.9yrs BRRA group and 12.2yrs RA group. All components of DAS28-CRP except VAS were significantly higher in the BRRA group (Table 1). Autoantibody positivity in the BRRA group was significantly higher, 19 (95%) were positive for RF compared to 13 (65%) in the RA group (p=0.044) and 18 (90%) were positive for ACPA compared to 11 (55%) in the RA group (p=0.031). Where hand and foot x-rays were available, 9/15 BRRA (60%) and 6/15 (40%) RA had evidence of erosive change. There was no significant difference (p=0.75) in the proportion of patients on combination therapy with ≥ one disease modifying drug/biologic, 9/20 BRRA (45%) and 7/20 RA (35%). Conclusions Patients with BRRA have higher DAS28-CRP and autoantibody positivity than those with RA alone. All components of DAS28-CRP, except the VAS (global) were significantly higher in the BRRA group demonstrating that the increase does not simply reflect higher CRP secondary to recurrent respiratory infections. Although numbers were too small to prove significance, an increased proportion of BRRA patients had erosive radiological change. Despite these findings DMARD/Biologic treatment was no more aggressive in the BRRA group suggesting under treatment of RA. It is likely this reflects concerns DMARD/Biologic treatment may exacerbate respiratory infections. There is currently no consensus on how to treat this challenging patient group, further studies are urgently required. References . McMahon et al. Bronchiectasis and rheumatoid arthritis a clinical study. Ann Rheum Dis 1993;52:776-779. . Cortet et al. Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis 1997;56:596-600.

Background: Immunoassays measuring antibodies to synthetic cyclic citrullinated peptides (CCP) ca... more Background: Immunoassays measuring antibodies to synthetic cyclic citrullinated peptides (CCP) capture anti-citrullinated protein/peptide antibodies (ACPAs) with a spectrum of fine specificities including naturally occurring citrullinated auto antigens. It has recently been demonstrated that the pathogenic association between HLA-DRB1SE, PTPN22 and smoking is strongest for the RA subset that carry antibodies to native citrullinated peptides, a-enolase and vimentin. Furthermore, enhanced citrullinated peptide expression in lungs of smokers supports the hypothesis that autoimmunity in RA can be initiated during lung inflammation. The association between bronchiectasis (BR) and RA is well recognized, despite this the pathogenesis is unknown. We hypothesize that similar to smoking, lung inflammation/ infection in susceptible individuals with BR may result in the exposure of the native citrullinated peptides, development of autoantibodies and in selected patients initiate the autoimmunit...