Fiona Goldblatt - Academia.edu (original) (raw)
Papers by Fiona Goldblatt
Handbook of experimental pharmacology, 2008
Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheu... more Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheumatic diseases. In the last few years, evolution in the understanding of RA and SLE pathogenesis and underlying molecular mechanisms has resulted in development and availability of novel therapies. In particular, the recent acknowledgement of a more significant role for B cells in the pathogenesis of RA, in contrast to the view that it was predominantly a T cell disorder, provided rationale for trials of B cell depletion therapy with the chimeric anti-CD20 monoclonal antibody rituximab. The efficacy and favourable safety profile of rituximab have resulted in the recent approval by the European Medicines Agency for its usage in patients with RA unresponsive to conventional therapies. The salient features from the pivotal open and randomised controlled trials are reviewed in this chapter. Given the recognition of B cell dysfunction as central to SLE pathogenesis, the use of anti-CD20 antib...
Rheumatology, 2009
To determine whether opsonization of Streptococcus pneumoniae with C3b/iC3b is impaired in serum ... more To determine whether opsonization of Streptococcus pneumoniae with C3b/iC3b is impaired in serum from patients with SLE. The ability of serum samples from 30 patients with SLE, 20 with non-SLE rheumatic diseases (RA, PsA, AS, SS) and 20 healthy controls to opsonize S. pneumoniae (strains D39 and Io11697) with C3b/iC3b was assessed using a standardized FACS technique and a FACSCalibur flow cytometer. Results were compared among the three groups using analysis of variance, followed by pairwise comparisons among groups using the Mann-Whitney U-test. The proportion of bacteria positive for C3b/iC3b was significantly lower in serum from patients with SLE (strain D39: 60.3% +/- s.e.m. 2.87, strain Io11697: 55.3% +/- 3.8) compared with healthy controls (strain D39: 70.6% +/- 2.0, P = 0.01; strain Io11697: 67.8% +/- 2.6; P = 0.05) and non-SLE rheumatic controls (strain D39: 69.8% +/- 3.1; P = 0.03). For the patients with SLE, there was no association between C3b/iC3b deposition and serum complement levels or measurable classical pathway activity. C3b/iC3b deposition on S. pneumoniae was significantly lower in serum from SLE patients with a past history of pneumonia (n = 3) compared with those without (n = 27; P = 0.03). Opsonization of S. pneumoniae with C3b/iC3b was significantly reduced in serum from patients with SLE compared with non-SLE rheumatic disease and healthy controls. Failure to appropriately activate the immune system via complement may contribute to the increased susceptibility of SLE subjects to infections, and may correlate with a risk of pneumonia in a subgroup of SLE patients.
Rheumatology, 2007
... systemic lupus erythematosus. Lupus 1991;1:37-41. Abstract/FREE Full Text. ↵: Kucukardali Y,;... more ... systemic lupus erythematosus. Lupus 1991;1:37-41. Abstract/FREE Full Text. ↵: Kucukardali Y,; Solmazgul E,; Kunter E,; Oncul O,; Yildirim S,; Kaplan M. . Kikuchi-Fujimotos disease: analysis of 244 cases. Clin Rheumatol 2007;26 ...
Lupus, 2009
This retrospective study determined the prevalence and nature of hospitalisations secondary to in... more This retrospective study determined the prevalence and nature of hospitalisations secondary to infection, and examined the mortality from infection in our large British cohort of patients with systemic lupus erythematosus (SLE). Casenote and database information of 104 consecutive patients attending the UCLH specialised SLE clinic were reviewed for the number of hospitalisations due to infection and the clinical and serological features of affected patients. Cohort mortality data were examined to identify deaths secondary to infectious diseases. Infection serious enough to result in hospitalisation occurred in 15% of the patients in the selected sample of our whole cohort. Six patients had more than one admission due to infection, with pneumonia being the most frequent. Typical bacterial pathogens were most commonly identified. A significant association between admissions for infection and nephritis (P < 0.05 by Chi-square) was identified; however, the use of high dose prednisolo...
Seminars in Arthritis and Rheumatism, 2007
To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA... more To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. At baseline, subjects had at least moderately active disease (mean +/- SD DAS28 was 5.3 +/- 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 +/- 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.
Rheumatology, 2007
... systemic lupus erythematosus. Lupus 1991;1:37-41. Abstract/FREE Full Text. ↵: Kucukardali Y,;... more ... systemic lupus erythematosus. Lupus 1991;1:37-41. Abstract/FREE Full Text. ↵: Kucukardali Y,; Solmazgul E,; Kunter E,; Oncul O,; Yildirim S,; Kaplan M. . Kikuchi-Fujimotos disease: analysis of 244 cases. Clin Rheumatol 2007;26 ...
Internal Medicine Journal, 2008
Background: The presence of sicca symptoms is a frequent finding in patients with systemic sclero... more Background: The presence of sicca symptoms is a frequent finding in patients with systemic sclerosis (SSc). The aim of this study was to examine the prevalence of sicca symptoms in a South Australian cohort of SSc patients and correlate this to a number of parameters, including autoantibody status, use of anticholinergic medication, age and the presence of functional antimuscarinic-3 receptor (M3R)-blocking antibodies.
Autoimmunity, 2002
Pemphigus is a clinically important autoimmune skin disease characterised by intercellular substa... more Pemphigus is a clinically important autoimmune skin disease characterised by intercellular substance antibodies, detected by indirect immunofluorescence on monkey oesphagus tissue. It has been observed that anti-A and anti-B blood group antibodies can produce staining patterns similar to that seen in pemphigus, yet this potential problem is not well recognised. We have demonstrated false positive pemphigus staining with blood group O sera and describe features by fluorescence and confocal microscopy, which may be useful in distinguishing true from false positive pemphigus staining.
Nature reviews. Drug discovery, 2009
Infection and immunity, 2008
Results from studies using mice deficient in specific complement factors and clinical data on pat... more Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3...
Journal of autoimmunity, 2015
Recent advances in mass spectrometry-based proteomic methods have allowed variable (V)-region pep... more Recent advances in mass spectrometry-based proteomic methods have allowed variable (V)-region peptide signatures to be derived from human autoantibodies present in complex serum mixtures. Here, we analysed the clonality and V-region composition of immunoglobulin (Ig) proteomes specific for the immunodominant SmD protein subunit of the lupus-specific Sm autoantigen. Precipitating SmD-specific IgGs were eluted from native SmD-coated ELISA plates preincubated with sera from six patients with systemic lupus erythematosus (SLE) positive for anti-Sm/RNP. Heavy (H)- and light (L)-chain clonality and V-region sequences were analysed by 2-dimensional gel electrophoresis and combined de novo database mass spectrometric sequencing. SmD autoantibody proteomes from all six patients with SLE expressed IgG1 kappa restricted clonotypes specified by IGHV3-7 and IGHV1-69 H-chains and IGKV3-20 and IGKV2-28 L-chains, with shared and individual V-region amino acid replacement mutations. Clonotypic shari...
A Clinician's Pearls and Myths in Rheumatology, 2009
Seminars in Arthritis and Rheumatism, 2007
To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA... more To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. At baseline, subjects had at least moderately active disease (mean +/- SD DAS28 was 5.3 +/- 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 +/- 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.
Rheumatology, 2008
Objective. To validate a tool for assessment of accumulated damage in patients with Primary SS (P... more Objective. To validate a tool for assessment of accumulated damage in patients with Primary SS (PSS). Methods. Of the total 114 patients fulfilling American-European Consensus Group (AECG) criteria for PSS 104 were included in the study and assessed by rheumatologists at T (time) ¼ 0 months and T ¼ 12 months. On each occasion, damage and activity data, and autoantibody status were collected. SF-36 and Profile of Fatigue and Discomfort-Sicca Symptoms Inventory (PROFAD-SSI) questionnaires were completed. Cross-sectional analysis of this data was subject to a process of expert validation by 11 ophthalmologists, 14 oral medicine specialists and 8 rheumatologists. Items were removed from the index if ! 50% of respondents recommended exclusion. Statistical validation was performed on remaining items. Spearman's rank analysis was used to investigate associations between damage scores and other disease status measures and Wilcoxon matched-pair analysis to assess sensitivity to change in the damage score.
Rheumatology, 2007
This article describes the development of the Sjögren&amp;#39;s Systemic Clinical Activit... more This article describes the development of the Sjögren&amp;#39;s Systemic Clinical Activity Index (SCAI) for the measurement of systemic disease activity in patients with primary Sjögren&amp;#39;s syndrome (PSS). A pilot tool was developed based on expert consensus and previous published data. One hundred and four patients with PSS were evaluated in a cross-sectional analysis, of whom 65 were reviewed at 3-monthly intervals, using this index, over a 12-month period. Factor analysis was used to evaluate the proposed domain structure. External validation was assessed by comparison with relevant domains of the Profile of Fatigue and Discomfort (PROFAD), Medical Outcomes Study Short Form-36 (SF-36) and The World Health Organization Quality of Life-Bref (WHOQOL-BREF). Sensitivity to change was assessed by comparing SCAI-derived flares with physician-designated disease flare and intention-to-treat analysis. A reliability and repeatability workshop was also held. Factor analysis supported the proposed domain structure. There were strong correlations between the SCAI fatigue, musculoskeletal and Raynaud&amp;#39;s components and the PROFAD fatigue, arthralgia and vascular domains. There was a significant correlation between change in therapy and SCAI-defined flares (P = 0.01). The mean kappa-test results both for reliability of the SCAI and for physician repeatability were 0.71. This initial evaluation supports the potential for the SCAI as a tool for systemic activity assessment in patients with PSS but additional work is required to assess sensitivity to change in clinical therapeutic trials.
The Lancet, 2013
Multisystem autoimmune rheumatic diseases are heterogeneous rare disorders associated with substa... more Multisystem autoimmune rheumatic diseases are heterogeneous rare disorders associated with substantial morbidity and mortality. Efforts to create international consensus within the past decade have resulted in the publication of new classification or nomenclature criteria for several autoimmune rheumatic diseases, specifically for systemic lupus erythematosus, Sjögren&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s syndrome, and the systemic vasculitides. Substantial progress has been made in the formulation of new criteria in systemic sclerosis and idiopathic inflammatory myositis. Although the autoimmune rheumatic diseases share many common features and clinical presentations, differentiation between the diseases is crucial because of important distinctions in clinical course, appropriate drugs, and prognoses. We review some of the dilemmas in the diagnosis of these autoimmune rheumatic diseases, and focus on the importance of new classification criteria, clinical assessment, and interpretation of autoimmune serology. In this era of improvement of mortality rates for patients with autoimmune rheumatic diseases, we pay particular attention to the effect of leading complications, specifically cardiovascular manifestations and cancer, and we update epidemiology and prognosis.
The Journal of Rheumatology, 2010
To estimate the indirect costs associated with primary Sjögren&amp;amp;amp;amp;amp;amp;am... more To estimate the indirect costs associated with primary Sjögren&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s syndrome (pSS) compared with rheumatoid arthritis (RA) and community controls. Data were obtained from 84 women patients with pSS as part of a study to develop a systemic activity measure, from 87 consecutive women patients with RA attending a hospital clinic, and from 96 women community controls on a general practice list. A modified economic component of the Stanford Health Assessment Questionnaire was used to assess lost productivity. Using a conservative model, the estimated total annual indirect costs (95% CI) were 7677 pound sterling (5560 pound sterling, 9794 pound sterling) for pSS, 10,444 pound sterling (8206 pound sterling, 12,681 pound sterling) for RA, and 892 pound sterling (307 pound sterling, 1478 pound sterling) for controls. Using a model that maximizes the estimates, the equivalent figures were 13,502 pound sterling (9542 pound sterling, 17,463 pound sterling), 17,070 pound sterling (13,112 pound sterling, 21,028 pound sterling), and 3382 pound sterling (2187 pound sterling, 4578 pound sterling), respectively. These were all significantly greater at p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001 for patient groups than for the control group. pSS is associated with significantly increased indirect costs equivalent to 69%-83% of that for patients with RA. This needs to be taken into account when evaluating the overall economic consequences of pSS.
Infection and Immunity, 2008
Results from studies using mice deficient in specific complement factors and clinical data on pat... more Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3b-iC3b deposition onto cells of all three serotypes of S. pneumoniae and seems to be more important than the alternative pathway for phagocytosis. Compared to the results for sera from normal subjects, C3b-iC3b deposition and total anti-S. pneumoniae antibody activity levels in sera obtained from C2 ؊/؊ subjects were reduced and the efficiency of phagocytosis of all three S. pneumoniae strains was impaired. Anticapsular antibody levels did not correlate with phagocytosis or C3b-iC3b deposition. These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections.
Gastroenterology, 2002
Abbreviations used in this paper: NK, neurokinin; RA, rheumatoid arthritis; RF, rheumatoid factor... more Abbreviations used in this paper: NK, neurokinin; RA, rheumatoid arthritis; RF, rheumatoid factor; VGCC, voltage-gated calcium channel.
Handbook of experimental pharmacology, 2008
Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheu... more Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheumatic diseases. In the last few years, evolution in the understanding of RA and SLE pathogenesis and underlying molecular mechanisms has resulted in development and availability of novel therapies. In particular, the recent acknowledgement of a more significant role for B cells in the pathogenesis of RA, in contrast to the view that it was predominantly a T cell disorder, provided rationale for trials of B cell depletion therapy with the chimeric anti-CD20 monoclonal antibody rituximab. The efficacy and favourable safety profile of rituximab have resulted in the recent approval by the European Medicines Agency for its usage in patients with RA unresponsive to conventional therapies. The salient features from the pivotal open and randomised controlled trials are reviewed in this chapter. Given the recognition of B cell dysfunction as central to SLE pathogenesis, the use of anti-CD20 antib...
Rheumatology, 2009
To determine whether opsonization of Streptococcus pneumoniae with C3b/iC3b is impaired in serum ... more To determine whether opsonization of Streptococcus pneumoniae with C3b/iC3b is impaired in serum from patients with SLE. The ability of serum samples from 30 patients with SLE, 20 with non-SLE rheumatic diseases (RA, PsA, AS, SS) and 20 healthy controls to opsonize S. pneumoniae (strains D39 and Io11697) with C3b/iC3b was assessed using a standardized FACS technique and a FACSCalibur flow cytometer. Results were compared among the three groups using analysis of variance, followed by pairwise comparisons among groups using the Mann-Whitney U-test. The proportion of bacteria positive for C3b/iC3b was significantly lower in serum from patients with SLE (strain D39: 60.3% +/- s.e.m. 2.87, strain Io11697: 55.3% +/- 3.8) compared with healthy controls (strain D39: 70.6% +/- 2.0, P = 0.01; strain Io11697: 67.8% +/- 2.6; P = 0.05) and non-SLE rheumatic controls (strain D39: 69.8% +/- 3.1; P = 0.03). For the patients with SLE, there was no association between C3b/iC3b deposition and serum complement levels or measurable classical pathway activity. C3b/iC3b deposition on S. pneumoniae was significantly lower in serum from SLE patients with a past history of pneumonia (n = 3) compared with those without (n = 27; P = 0.03). Opsonization of S. pneumoniae with C3b/iC3b was significantly reduced in serum from patients with SLE compared with non-SLE rheumatic disease and healthy controls. Failure to appropriately activate the immune system via complement may contribute to the increased susceptibility of SLE subjects to infections, and may correlate with a risk of pneumonia in a subgroup of SLE patients.
Rheumatology, 2007
... systemic lupus erythematosus. Lupus 1991;1:37-41. Abstract/FREE Full Text. ↵: Kucukardali Y,;... more ... systemic lupus erythematosus. Lupus 1991;1:37-41. Abstract/FREE Full Text. ↵: Kucukardali Y,; Solmazgul E,; Kunter E,; Oncul O,; Yildirim S,; Kaplan M. . Kikuchi-Fujimotos disease: analysis of 244 cases. Clin Rheumatol 2007;26 ...
Lupus, 2009
This retrospective study determined the prevalence and nature of hospitalisations secondary to in... more This retrospective study determined the prevalence and nature of hospitalisations secondary to infection, and examined the mortality from infection in our large British cohort of patients with systemic lupus erythematosus (SLE). Casenote and database information of 104 consecutive patients attending the UCLH specialised SLE clinic were reviewed for the number of hospitalisations due to infection and the clinical and serological features of affected patients. Cohort mortality data were examined to identify deaths secondary to infectious diseases. Infection serious enough to result in hospitalisation occurred in 15% of the patients in the selected sample of our whole cohort. Six patients had more than one admission due to infection, with pneumonia being the most frequent. Typical bacterial pathogens were most commonly identified. A significant association between admissions for infection and nephritis (P < 0.05 by Chi-square) was identified; however, the use of high dose prednisolo...
Seminars in Arthritis and Rheumatism, 2007
To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA... more To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. At baseline, subjects had at least moderately active disease (mean +/- SD DAS28 was 5.3 +/- 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 +/- 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.
Rheumatology, 2007
... systemic lupus erythematosus. Lupus 1991;1:37-41. Abstract/FREE Full Text. ↵: Kucukardali Y,;... more ... systemic lupus erythematosus. Lupus 1991;1:37-41. Abstract/FREE Full Text. ↵: Kucukardali Y,; Solmazgul E,; Kunter E,; Oncul O,; Yildirim S,; Kaplan M. . Kikuchi-Fujimotos disease: analysis of 244 cases. Clin Rheumatol 2007;26 ...
Internal Medicine Journal, 2008
Background: The presence of sicca symptoms is a frequent finding in patients with systemic sclero... more Background: The presence of sicca symptoms is a frequent finding in patients with systemic sclerosis (SSc). The aim of this study was to examine the prevalence of sicca symptoms in a South Australian cohort of SSc patients and correlate this to a number of parameters, including autoantibody status, use of anticholinergic medication, age and the presence of functional antimuscarinic-3 receptor (M3R)-blocking antibodies.
Autoimmunity, 2002
Pemphigus is a clinically important autoimmune skin disease characterised by intercellular substa... more Pemphigus is a clinically important autoimmune skin disease characterised by intercellular substance antibodies, detected by indirect immunofluorescence on monkey oesphagus tissue. It has been observed that anti-A and anti-B blood group antibodies can produce staining patterns similar to that seen in pemphigus, yet this potential problem is not well recognised. We have demonstrated false positive pemphigus staining with blood group O sera and describe features by fluorescence and confocal microscopy, which may be useful in distinguishing true from false positive pemphigus staining.
Nature reviews. Drug discovery, 2009
Infection and immunity, 2008
Results from studies using mice deficient in specific complement factors and clinical data on pat... more Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3...
Journal of autoimmunity, 2015
Recent advances in mass spectrometry-based proteomic methods have allowed variable (V)-region pep... more Recent advances in mass spectrometry-based proteomic methods have allowed variable (V)-region peptide signatures to be derived from human autoantibodies present in complex serum mixtures. Here, we analysed the clonality and V-region composition of immunoglobulin (Ig) proteomes specific for the immunodominant SmD protein subunit of the lupus-specific Sm autoantigen. Precipitating SmD-specific IgGs were eluted from native SmD-coated ELISA plates preincubated with sera from six patients with systemic lupus erythematosus (SLE) positive for anti-Sm/RNP. Heavy (H)- and light (L)-chain clonality and V-region sequences were analysed by 2-dimensional gel electrophoresis and combined de novo database mass spectrometric sequencing. SmD autoantibody proteomes from all six patients with SLE expressed IgG1 kappa restricted clonotypes specified by IGHV3-7 and IGHV1-69 H-chains and IGKV3-20 and IGKV2-28 L-chains, with shared and individual V-region amino acid replacement mutations. Clonotypic shari...
A Clinician's Pearls and Myths in Rheumatology, 2009
Seminars in Arthritis and Rheumatism, 2007
To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA... more To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. At baseline, subjects had at least moderately active disease (mean +/- SD DAS28 was 5.3 +/- 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 +/- 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.
Rheumatology, 2008
Objective. To validate a tool for assessment of accumulated damage in patients with Primary SS (P... more Objective. To validate a tool for assessment of accumulated damage in patients with Primary SS (PSS). Methods. Of the total 114 patients fulfilling American-European Consensus Group (AECG) criteria for PSS 104 were included in the study and assessed by rheumatologists at T (time) ¼ 0 months and T ¼ 12 months. On each occasion, damage and activity data, and autoantibody status were collected. SF-36 and Profile of Fatigue and Discomfort-Sicca Symptoms Inventory (PROFAD-SSI) questionnaires were completed. Cross-sectional analysis of this data was subject to a process of expert validation by 11 ophthalmologists, 14 oral medicine specialists and 8 rheumatologists. Items were removed from the index if ! 50% of respondents recommended exclusion. Statistical validation was performed on remaining items. Spearman's rank analysis was used to investigate associations between damage scores and other disease status measures and Wilcoxon matched-pair analysis to assess sensitivity to change in the damage score.
Rheumatology, 2007
This article describes the development of the Sjögren&amp;#39;s Systemic Clinical Activit... more This article describes the development of the Sjögren&amp;#39;s Systemic Clinical Activity Index (SCAI) for the measurement of systemic disease activity in patients with primary Sjögren&amp;#39;s syndrome (PSS). A pilot tool was developed based on expert consensus and previous published data. One hundred and four patients with PSS were evaluated in a cross-sectional analysis, of whom 65 were reviewed at 3-monthly intervals, using this index, over a 12-month period. Factor analysis was used to evaluate the proposed domain structure. External validation was assessed by comparison with relevant domains of the Profile of Fatigue and Discomfort (PROFAD), Medical Outcomes Study Short Form-36 (SF-36) and The World Health Organization Quality of Life-Bref (WHOQOL-BREF). Sensitivity to change was assessed by comparing SCAI-derived flares with physician-designated disease flare and intention-to-treat analysis. A reliability and repeatability workshop was also held. Factor analysis supported the proposed domain structure. There were strong correlations between the SCAI fatigue, musculoskeletal and Raynaud&amp;#39;s components and the PROFAD fatigue, arthralgia and vascular domains. There was a significant correlation between change in therapy and SCAI-defined flares (P = 0.01). The mean kappa-test results both for reliability of the SCAI and for physician repeatability were 0.71. This initial evaluation supports the potential for the SCAI as a tool for systemic activity assessment in patients with PSS but additional work is required to assess sensitivity to change in clinical therapeutic trials.
The Lancet, 2013
Multisystem autoimmune rheumatic diseases are heterogeneous rare disorders associated with substa... more Multisystem autoimmune rheumatic diseases are heterogeneous rare disorders associated with substantial morbidity and mortality. Efforts to create international consensus within the past decade have resulted in the publication of new classification or nomenclature criteria for several autoimmune rheumatic diseases, specifically for systemic lupus erythematosus, Sjögren&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s syndrome, and the systemic vasculitides. Substantial progress has been made in the formulation of new criteria in systemic sclerosis and idiopathic inflammatory myositis. Although the autoimmune rheumatic diseases share many common features and clinical presentations, differentiation between the diseases is crucial because of important distinctions in clinical course, appropriate drugs, and prognoses. We review some of the dilemmas in the diagnosis of these autoimmune rheumatic diseases, and focus on the importance of new classification criteria, clinical assessment, and interpretation of autoimmune serology. In this era of improvement of mortality rates for patients with autoimmune rheumatic diseases, we pay particular attention to the effect of leading complications, specifically cardiovascular manifestations and cancer, and we update epidemiology and prognosis.
The Journal of Rheumatology, 2010
To estimate the indirect costs associated with primary Sjögren&amp;amp;amp;amp;amp;amp;am... more To estimate the indirect costs associated with primary Sjögren&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s syndrome (pSS) compared with rheumatoid arthritis (RA) and community controls. Data were obtained from 84 women patients with pSS as part of a study to develop a systemic activity measure, from 87 consecutive women patients with RA attending a hospital clinic, and from 96 women community controls on a general practice list. A modified economic component of the Stanford Health Assessment Questionnaire was used to assess lost productivity. Using a conservative model, the estimated total annual indirect costs (95% CI) were 7677 pound sterling (5560 pound sterling, 9794 pound sterling) for pSS, 10,444 pound sterling (8206 pound sterling, 12,681 pound sterling) for RA, and 892 pound sterling (307 pound sterling, 1478 pound sterling) for controls. Using a model that maximizes the estimates, the equivalent figures were 13,502 pound sterling (9542 pound sterling, 17,463 pound sterling), 17,070 pound sterling (13,112 pound sterling, 21,028 pound sterling), and 3382 pound sterling (2187 pound sterling, 4578 pound sterling), respectively. These were all significantly greater at p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001 for patient groups than for the control group. pSS is associated with significantly increased indirect costs equivalent to 69%-83% of that for patients with RA. This needs to be taken into account when evaluating the overall economic consequences of pSS.
Infection and Immunity, 2008
Results from studies using mice deficient in specific complement factors and clinical data on pat... more Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3b-iC3b deposition onto cells of all three serotypes of S. pneumoniae and seems to be more important than the alternative pathway for phagocytosis. Compared to the results for sera from normal subjects, C3b-iC3b deposition and total anti-S. pneumoniae antibody activity levels in sera obtained from C2 ؊/؊ subjects were reduced and the efficiency of phagocytosis of all three S. pneumoniae strains was impaired. Anticapsular antibody levels did not correlate with phagocytosis or C3b-iC3b deposition. These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections.
Gastroenterology, 2002
Abbreviations used in this paper: NK, neurokinin; RA, rheumatoid arthritis; RF, rheumatoid factor... more Abbreviations used in this paper: NK, neurokinin; RA, rheumatoid arthritis; RF, rheumatoid factor; VGCC, voltage-gated calcium channel.