Pulmonary fibrosis in polymyositis with the Jo-1 syndrome: an unusual mode of presentation.
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Biomedical subjects
Publications and source records attributed to B Bresnihan.
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Previous studies have used various techniques for microscopic analysis of rheumatoid synovium, ranging from rapid analysis of limited areas of tissue to detailed quantification of extensive areas. The sensitivity and reproducibility of these methods have not been tested. This study sought to determine the minimum area of rheumatoid synovium needed to allow accurate microscopic analysis of synovial inflammation. Multiple synovial tissue samples were obtained from patients with rheumatoid arthritis at knee arthroplasty (n = 10), knee arthroscopy (n = 10) and by blind needle biopsy (n = 23). Lining layer thickness, sublining T-cell infiltration and vascularity were measured in all high-power fields (hpf) throughout every sample obtained from each patient. These complete measured results were compared with estimated results from limited numbers of hpf from each patient. It was observed that lining layer thickness estimated from as few as five readings from 3 samples/patient correlated significantly with the measured results obtained from as many as 85 readings/patient [Tau (T) = 0.70-0.94 for the three groups, all P < or = 0.005). Estimated measures of T-cell infiltration and vascularity derived from only 17 randomly selected hpf from 3 samples/patient (equivalent to 1 mm2) correlated significantly with the measured results obtained from up to 150 hpf/patient (T = 0.65-0.94, all P < or = 0.002). Quantitative analysis of inflammation in synovial tissue samples is both accurate and practical when restricted to an evaluation of a limited number of microscopic fields. It is proposed that lining layer thickness may be confidently quantified from five randomly selected readings from three tissue samples, and that sublining T-cell infiltration and vascularity may be quantified from 17 randomly selected hpf from the same samples.
Microscopic measurement of inflammation in synovial tissue may be important in studies of clinical status, prognosis and response to treatment. The aim of this study was to compare quantitative microscopic analysis of inflammation with a semiquantitative grading system in rheumatoid arthritis (RA) synovial membrane. Knee synovial membrane samples from 16 patients with RA, including paired samples taken before and after treatment in nine patients, were immunostained with anti-CD68 and anti-CD3 monoclonal antibodies using standard techniques. The intensity of macrophage and T-lymphocyte infiltration was measured both by quantitative and semiquantitative techniques, and the results were compared. In a cross-sectional comparison, both methods correlated significantly for lining layer macrophage infiltration, as well as sublining layer macrophage and T-cell infiltration. However, in some patients demonstrating a clinical response to treatment, semiquantitative analysis lacked sensitivity to biologically relevant changes in mononuclear cell infiltration. These observations have important implications for future studies of therapeutic modalities.
OBJECTIVE: To determine the effect of ultrasound guided injection in recalcitrant idiopathic plantar fasciitis. METHODS: Four patients with a clinical diagnosis of idiopathic plantar fasciitis, who were unresponsive to palpation guided injection with triamcinolone acetonide and local anaesthetic, underwent ultrasonographic examination of the heel. RESULTS: The following ultrasonographic features were noted:- (a) increased thickness of plantar fascia in symptomatic heels compared with asymptomatic heels, (b) loss of distinction of the distal plantar fascia borders, (c) reduced echogenicity of the plantar fascia. Ultrasound guided injection of the enlarged, hypoechoic plantar fascia resulted in complete relief in four of five heels (mean duration of follow up = 24 months) in three cases. One patient developed a recurrence of symptoms after six months. CONCLUSION: Ultrasound allows for confirmation of the clinical diagnosis and ultrasound guided injection produces a good clinical response when unguided injection is unsuccessful. The technique is quick, inexpensive, and entails no radiation exposure.
We describe the first case of catastrophic antiphospholipid antibody syndrome (APS) in a patient with progressive systemic sclerosis (SSc). After initial presentation with digital gangrene the patient developed rapidly progressive multiorgan failure and died within 19 hours. Postmortem examination revealed extensive multiorgan arterial microthrombi of days' to months' duration. This suggests that a subclinical state of thrombosis existed before onset of catastrophic APS. Given the poor prognosis of established catastrophic APS there is a need for a means to detect subclinical thrombosis and treat "at risk" patients before clinically apparent thrombosis occurs.
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OBJECTIVE: To study the effect of accuracy on the clinical outcome of local steroid injections to the shoulder. METHODS: 37 patients with shoulder symptoms of at least two months' duration received local injections of a mixture of triamcinolone and radiographic contrast material using a standardised technique. Radiographs of the joint were taken immediately afterwards. Details of the patients' symptoms (assessed by visual analogue scales) and range of movement at the joint were obtained before and two weeks after the injection. At follow up the patients were also assessed by means of a five point global rating scale of maximum and current benefit. RESULTS: 14 of the 38 procedures (37%) were judged to be accurately placed: four of the 14 attempted subacromial injections (29%) and 10 of the 24 attempted glenohumeral injections (42%). There were significant differences in relation to outcome between the accurately placed and the inaccurately placed groups. CONCLUSIONS: Accuracy of steroid placement by injection in patients with shoulder symptoms may significantly affect the clinical outcome.
OBJECTIVE: To examine the relative contribution of individual synovial cell populations to polyarticular destruction in rheumatoid arthritis (RA). METHODS: Serial measurements of disease activity and articular destruction, obtained prospectively in 28 RA patients followed for a mean of 5.8 years, were correlated with synovial cell populations quantified using immunohistochemical techniques. RESULTS: The mean radiologic score worsened (from 37 to 86; P = 0.0001) despite significant improvement in disease activity. Synovial lining layer cell depth and sublining layer macrophage, but no lymphocyte, cell counts correlated significantly with radiologic course. Detailed analysis of 11 patients demonstrated reduced synovial lining expression of CD14 compared with CD68 (P = 0.003), whereas sublining expression of CD14 and CD68 was equivalent. CONCLUSION: Synovial macrophage numbers correlated with articular destruction in RA. In addition, the study results provided further evidence that lining layer macrophages may represent a distinct subpopulation that is of importance in this process. These findings have implications for the development of new therapies for RA.
Adhesion molecules play a critical role in regulating leucocyte migration at sites of inflammation. The relationship of soluble forms in serum or synovial fluid (SF) to synovial membrane expression in inflammatory arthritis is controversial. We examined soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin levels in matched serum and SF, and their relationship to expression in synovium obtained at the same time in 13 patients with previously untreated inflammatory arthritis. Serum-soluble (s)ICAM-1 correlated with sedimentation rate (T = 0.45), Ritchie articular index (T = 0.47) and SF sICAM-1 (T = 0.48), and SF sICAM-1 correlated with membrane ICAM-1 expression (p < 0.02). sE-selectin and sVCAM-1 levels were unrelated to disease activity or membrane expression. Membrane E-selectin expression correlated inversely with ICAM-1 expression (T = -0.57) and serum sICAM-1 (T = -0.54). Serum sE-selectin correlated inversely with membrane ICAM-1 expression (T = -0.55). The correlations observed between ICAM-1 in serum, SF, synovium and disease activity suggest that ICAM-1 could be a useful target for immunotherapy. The inverse relationship of ICAM-1 and E-selectin suggest important differences in regulation and pathogenetic roles.
The contrast between clinical improvement and radiological deterioration in rheumatoid arthritis (RA) is striking. We characterized this relationship using serial disease activity measures and radiographs of hands and feet in 40 RA patients observed over 6 yr. All disease activity measures improved, including grip strength, Ritchie index (RI), haemoglobin and erythrocyte sedimentation rate (ESR) (all P < 0.0001). In contrast, articular erosion increased (P < 0.0001). Radiological change during the study correlated with RI (r = 0.49), haemoglobin (r = -0.56) and ESR (r = 0.53). Radiological status at review also correlated with these variables (r = 0.36, -0.44 and 0.36, respectively). Articular erosion continues in RA despite clinical improvement and is accelerated in those with evidence of continuing synovial inflammation, reflected in clinical and laboratory measures of disease activity. Since many therapies in RA suppress inflammation, but not erosion, these findings suggest that the pathogenesis of articular erosion may differ from that of synovial inflammation.
Patients presenting with RA before the age of 45 years (younger onset) are known to have more aggressive disease compared with patients presenting after the age of 65 years (older onset). Coordinated expansion of circulating CD5+ B cell and TCR gamma delta+ T cell levels has been reported in patients with RA. This study assesses the peripheral blood levels of these two cell types in RA patients with younger and older onset of disease. CD5+ B cell levels were significantly elevated in the younger onset RA group (26.6+/-4.5%) compared with the older onset RA group (14.2+/-1.2%; P<0.01). TCR gamma delta+ T cell levels were also significantly raised in the young patients (4.0+/-0.9%) compared with elderly patients (1.6+/-0.2%; P<0.01). T cell levels (CD3+) were similar in both groups (young 66.4+/-3.3%; old 74.3+/-3.4% (mean+/-s.e.m.); NS). Total B cell levels (CD19+) were also similar in these groups (7.7+/-0.7% versus 8.9+/-1.8%; NS). A significant positive correlation was observed between the CD5+ B and TCR gamma delta+ T cell types in the patients (r=0.72, P<0.05). Compared with age-matched normal controls, the younger onset patients had similar CD5+ B cell and TCR gamma delta+ T cell levels to the elderly controls (CD5+ B cells 30.2+/-3.0%; TCR gamma delta+ T cells 3.0+/-0.8%). Conversely, older onset RA patients had CD5+ B cell levels similar to the young controls (12.3+/-1.9%). Spontaneous in vitro synthesis of immunoglobulins (IgM, IgA and IgG) and rheumatoid factors (IgM and IgA isotypes) were not significantly different in both patient groups. The coordinate expansion of circulating CD5+ B cells and gamma delta+ T cells seen in patients with RA presenting before 45 years of age and not after 65 years of age may suggest a potential role for these cells in more aggressive disease states.
Seventeen families, in which the diagnosis of SLE could be verified in two relatives, were included in the study. The diagnosis was made according to the revised 1982 ARA criteria. We compared the 34 cases of familial SLE in these 17 families with 34 non-familial SLE controls matched for age, sex, ethnicity and duration of disease. Comparisons were made for the presence of 26 clinical and 11 serological features. The frequency of clinical features was similar between the groups. The frequency of anti-Ro antibody was higher in the non-familial group (15 out of 34 compared to 6 out of 34, P = 0.036, McNemar's test), although this was not significant after application of Bonferoni's correction for the number of comparisons. No cases of familial IgA or familial complement deficiency were identified. It was noted that 10 of the 34 non-familial patients and only one of the familial patients had the combination of anti-Ro antibody and photosensitivity. The findings of this study support the hypothesis that familial SLE and non-familial SLE are the same clinical entity, although there are differences in the subtypes of disease.
OBJECTIVE: Anemia of chronic disorders (ACD) and iron deficiency are common features in rheumatoid arthritis (RA), but may be difficult to distinguish without marrow sampling, which is invasive, time consuming, and expensive. We sought simple laboratory measures that identified patients with absent marrow iron stores (iron deficiency). METHODS: 45 anemic patients with RA underwent marrow sampling in addition to a complete blood count and serum ferritin and iron saturation measurements. RESULTS: 47% of patients had iron deficiency. These patients had significantly lower mean corpuscular volume (MCV), serum ferritin, and iron saturation. A 3 step algorithm was developed using these laboratory variables to identify iron deficiency. This algorithm correctly classified 94% patients with iron deficiency and 85% with ACD. CONCLUSION: Our study demonstrates that iron deficiency may be reliably identified by measuring serum ferritin, MCV, and iron saturation in many patients with RA, thereby avoiding the trauma and expense of marrow sampling.
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OBJECTIVES: To analyse the mononuclear cell populations in synovial membrane biopsies obtained before treatment from patients with rheumatoid arthritis (RA) and to correlate the findings with the degree of joint damage occurring over one year. METHODS: Multiple needle biopsy specimens were obtained from inflamed knee joints on entry to the study. The tissue samples were examined using immunohistochemical techniques. The degree of joint damage was estimated using the Larsen radiological index. RESULTS: Twelve patients were studied. It was observed that there was a significant correlation between the number of synovial tissue macrophages and the degree of joint erosion over one year (r = 0.66; p = 0.04). The synovial lining layer contained large numbers of macrophages and the cellularity of the lining layer correlated significantly with the number of macrophages infiltrating the sublining areas (r = 0.65; p = 0.01). Finally, the cellularity of the lining layer correlated with the synovial fluid levels of interleukin-6 (r = 0.66; p = 0.04). The radiological course did not correlate with infiltrating T or B lymphocyte populations, but did correlate with other previously identified indicators of the clinical course, including a high index of disease activity and IgA rheumatoid factors levels. CONCLUSION: This study suggests that synovial tissue macrophages play a critical role in the pathogenesis of joint erosion in RA.
Patients with cystic fibrosis (CF) have a high prevalence of Pseudomonas aeruginosa infection which causes chronic infection of the mucosal surfaces of the lung. This results in recurrent immune stimulation and hypergammaglobulinemia. The present study examines the levels of circulating Ig classes, IgG and IgA subclasses in 13 adult patients with CF during acute pulmonary infection and post-exacerbation. Total serum IgG levels were raised in the patients during infection and post-treatment when compared to the normal range (mean +/- SEM: 17.21 +/- 1.4 g/l vs 16.45 +/- 1.5 g/l respectively; normal range 8-16 g/l). In contrast, total IgM (2.6 +/- 0.26 vs 2.69 +/- 2.74 g/l; normal range 0.6-2.8 g/l) and IgA levels (2.5 +/- 0.52 vs 2.41 +/- 0.48 g/l; normal range 0.5-4 g/l) remained unchanged when examined during all stages of the disease. Of the 13 patients studied, 69%, 39% and 31% had IgG, IgM and IgA levels respectively raised above the normal range values. The mean levels of individual IgG subclasses examined in this group of patients revealed values within the normal ranges, however IgG2 and IgG3 were increased in 31% and 46% of patients. Individual IgG3 levels fell in 77% (10/13) and IgG4 in 62% (8/13) of the patients post-exacerbation. With regard to IgA subclasses, significant reduction in the IgA1 levels were observed post treatment (3687 +/- 539 mg/l vs 2713 +/- 498 mg/l, p < 0.01). In contrast, IgA2 levels were increased from 279 +/- 49 mg/l to 421 +/- 69 mg/l, although statistical significance was not reached. Upon antibiotic treatment for infection, the findings in this study show that IgA1 which is susceptible to bacterial proteases is reduced with a concommitant increase in the protease resistant IgA2 subclass. Moreover, patients colonised with non-mucoid strains of P. aeroginosa had higher total IgA levels due to the raised IgA1 subclass whereas they had lower IgG levels due to low IgG2 and IgG4 subclasses.
OBJECTIVE: To describe neurologic and neurophysiologic (NP) outcome in patients with systemic lupus erythematosus (SLE) followed prospectively and to determine predictors of change in NP status. METHODS: Clinical examination, laboratory and NP tests (brain stem auditory and visual evoked responses, peripheral nerve conduction studies) were performed in 18 unselected patients with SLE attending a general rheumatology clinic at enrollment into the study (baseline) and after a 2-year (mean) period of followup. RESULTS: Fifty percent (9/18) and 83% (15/18) of patients had neurological abnormalities at baseline and followup, respectively, the most common of which were headache and peripheral neuropathy. NP abnormalities were found in 56% (10/18) and 61% (11/18) of patients at baseline and followup. The most frequent abnormalities at both visits were of peripheral nerve conduction [33% (6/18) and 56% (10/18), respectively] and abnormalities of brainstem and/or visual evoked responses were found in 28% (5/18) and 22% (4/18) of patients at both visits. At baseline, vasculitis was significantly increased in patients with NP abnormalities (p = 0.04). NP status deteriorated between visits in 8 patients (44%), 6 of whom acquired peripheral abnormalities. Improvement in NP status was only noted in patients (2/18, 11%) who had NP abnormalities restricted to the central nervous system. Associations were seen between elevated dsDNA antibodies, vasculitis, and lymphopenia, and the risk of acquiring new NP abnormalities. CONCLUSION: Patients with SLE had many neurological and NP abnormalities. NP deficits acquired were most often of peripheral nerve conduction. The ability to identify and classify clinical and subclinical neurological abnormalities in patients with SLE using NP tests may enhance our understanding and management of their neurological disease.