Abstract: Giant cell arteritis is characterized primarily by inflammation in certain large and medium-sized arteries. The major risk factors are age, female gender and Northern European descent. In this report we describe two cases of acute vision loss due to giant cell arteritis. In both cases the erythrocyte sedimentation rate (ESR) was below 50 mm/hr and the presenting complaint was foggy vision followed by acute blindness. The cases are to some extent different, for example in the former case the patient reported jaw claudication and ophthalmologic evaluation was consistent with anterior ischemic optic neuropathy. In the latter case there was narrowing and box-carring of blood cells in retinal arterioles, consistent with occlusion of the central retinal artery. This patient had recently finished a 2-year long treatment with glucocorticosteroids for polymyalgia rheumatica. The retina and the optic nerve do not survive for long without perfusion. If giant cell arteritis causes blindness in one eye there is significant risk for the other eye to go blind if no treatment is given. Corticosteroids can spare the other eye and suppress the underlying inflammatory disease process as well. It is vital to confirm the diagnosis of giant cell arteritis with a biopsy and start corticosteroid treatment as soon as possible, even before the biopsy is taken. Elfarsson A, Gudbjornsson B, Stefansson E. Giant cell arteritis - two cases with acute blindness. Icel Med J 2010; 96: kkkkfff. Keywords: Giant cell arteritis, Corticosteroids, Headache, Acute blindness, Anterior ischemic optic neuropathy, Central retinal artery occlusion. Correspondence: Einar Stefánsson, einarste@landspitali.is.
Abstract: PURPOSE: To examine the risk of thromboembolic cardiovascular events in users of coxibs and NSAIDs in a nationwide cohort. METHODS: Data were synchronised from three nationwide databases, the Icelandic Medicines Registry (IMR), The Icelandic National Patient Registry (INPR) and the Registry for Causes of Death at Statistics Iceland (RCD), for prescriptions for NSAIDs or coxibs with respect to hospitalisation for unstable angina pectoris, myocardial infarction and cerebral infarction over a 3-year period. The Cox proportional hazards model and Poisson regression were used to analyse the data. RESULTS: A total of 108,700 individuals received prescriptions for NSAIDs or coxibs (ATC code M01A), of whom 78,539 received one drug only (163,406 person-years). Among those receiving only one drug 426 individuals were discharged from hospital with endpoint diagnoses. In comparison to diclofenac, the incidence ratios, adjusted for age and gender, were significantly higher for cerebral infarction (2.13; 95% CI 1.54-2.97; P < 0.001), for myocardial infarction (1.77; 95% CI 1.34-2.32; P < 0.001) and for unstable angina pectoris (1.52; 95% CI 1.01-2.30; P = 0.047) for patients who used rofecoxib. For naproxen users, the incidence ratio was 1.46 for myocardial infarction (95% CI 1.03-2.07; P = 0.03), but was reduced in ibuprofen users (0.63; 95% CI 0.40-1.00; P = 0.05). The youngest users of rofecoxib (</=39 years) had the highest hazard ratio (HR) for cardiovascular events (8.34; P < 0.001), while those >/=60 years had a lower but still significantly elevated HR (1.35; P = 0.001). CONCLUSION: This Icelandic nationwide registry-based study amounting to 163,406 patient-years showed increased risk of cardiovascular events, i.e. cerebral infarction, myocardial infarction and unstable angina pectoris, among rofecoxib and naproxen users in comparison to diclofenac users. The added risk was most pronounced in young adults using rofecoxib.
Abstract: OBJECTIVE: We have studied the prevalence of PsA in Reykjavik, Iceland, in a population-based cohort, and using the Icelandic genealogy database we have estimated the risk ratio (RR) spanning five generations. METHODS: The national identification numbers of all 220 living Icelanders in Reykjavik known to have PsA were linked with the genealogy database. RRs for developing PsA were estimated in first-degree relatives (FDRs) to fifth-degree relatives of PsA cases. The kinship coefficient (KC) for PsA was also calculated. The control populations were 1000 and 10,000 sets of matched Icelandic subjects for each proband, respectively. RESULTS: FDRs to fourth-degree relatives of patients with PsA had RRs of 39, 12, 3.6 and 2.3, respectively (all P-values < 0.0001), reflecting a strong genetic component, whereas the fifth-degree relatives had an RR of 1.2 (P = 0.236). KCs of 5.0, 3.4, 1.7, 1.3, 1.0, 0.8 and 0.7 were observed for the first seven excluded meioses (all P-values < 0.0001), confirming the familial risk. CONCLUSIONS: Patients with PsA in Reykjavik, Iceland, are significantly more related to each other than to randomly sampled control subjects. This is in agreement with previous reports, but the present study examines the inheritance in more distantly related individuals. These findings indicate that in addition to a strong and complex genetic component in PsA, there is an important environmental contribution.
Abstract: BACKGROUND: Assessment of chest expansion is one of the measures of rib cage mobility recommended as "core set for assessing Ankylosing Spondylitis" (AS). A recently developed instrument for measuring respiratory movements is introduced. PURPOSE: To compare chest and abdominal wall movements in AS patients with those of controls using a newly developed instrument. STUDY DESIGN: A comparative study. PATIENT SAMPLE: Fourteen male AS patients were invited to the study. All subjects answered a standardized questionnaire concerning general health. OUTCOME MEASURES: Body height and weight and respiratory movements. METHODS: Upper and lower chest wall and abdominal motion was measured bilaterally for a period of 1 minute during deep breathing by using a new instrument based on a laser technique, The Respiratory Movement Measuring Instrument (ReMo, ReykjavÃk, Iceland). Results were compared to healthy controls matched for age, gender, and body mass index. RESULTS: The patients' mean age was 47+/-9.5 years, and they had a history of AS for 13+/-6 years. Their mean BMI was 27+/-3.6. The respiratory movements of the upper thoracic level were significantly lower than in the reference group (right p=.01, left p=.05). They had, however, a normal range of lower thoracic and abdominal movement and their respiratory movement patterns were symmetrical. CONCLUSION: The AS patients had reduced upper thoracic movements but normal lower thoracic and abdominal wall movements.
Abstract: OBJECTIVE: To determine the prevalence, demographics, and course of psoriatic arthritis (PsA) in the Reykjavik area of Iceland. METHODS: In total 220 patients >/= 18 years of age living in the Reykjavik area of Iceland were located in a community registry of psoriatic patients and in hospital records. Of these, 156 (71%) were interviewed and examined for verification of skin and joint disease according to published criteria. RESULTS: Prevalence of PsA in the adult population was estimated to be 164 per 100,000 (95% CI 143-187), adjusted to 139 per 100,000 (95% CI 112-169) after exclusion of 25 individuals. The female to male ratio was close to 2:1. The mean age at skin disease onset was 23 years, with significantly earlier onset in women (age 20 yrs in women vs 26 yrs in men; p = 0.01), but there was no significant difference for age at the time of onset of joint disease. Mean duration of PsA was 20 years. Oligoarthritis was the most common (44%), followed by polyarthritis (31%), enthesitis (8%), and inflammatory back pain (7%). According to patients' recall of clinical features at onset, 78 patients (60%) had changed categories of PsA at the time of the study, most frequently from polyarthritis to oligoarthritis (48%), followed by oligoarthritis to polyarthritis (36%). These changes seemed independent of use of disease modifying drugs, which 54% had received. CONCLUSION: PsA in Reykjavik, Iceland, has a prevalence of at least 0.14% and is strikingly more common in women. The majority of patients reported a change in the pattern of affected joints during the course of their disease.
Abstract: Our objective was to investigate the initiation and course of pro- and anti-inflammatory cytokines in early inflammatory response and to elucidate the cytokine system in relation to the adrenal response caused by stress. Seven blood samples were collected, pre- and postoperatively (0-72 h) after total hip replacement (THR) due to osteoarthritis. The following cytokines were measured using Cytometric Bead Array: interleukin-1beta (IL-1beta), IL-6, tumour necrosis factor-alpha, IL-8, IL-12 and IL-10 (B&D). Thirteen patients took part in the study (67 +/- 9 years). C-reactive protein increased from <6 to over 200 mg/l on the second post-op day. The concentration of IL-6 increased 10-fold just 3 h post-op (4-47 pg/ml) and reached its maximum value 6 h post-op (77 pg/ml; Wilcoxon test P < 0.01) Repeated measurements were also significant (Friedman P < 0.05). The concentration of IL-8 doubled the day of surgery but did not reach a significant level (Friedman test =0.069). None of the other cytokines showed any significant changes. The diurnal cortisol rhythm was interrupted after the surgery and there was a significant correlation between the cortisol secretion and IL-6 response. This study demonstrates an isolated elevation in IL-6 levels with only a minor elevation in IL-8 following THR. This pro-inflammatory response seemed to decline without activation of anti-inflammatory cytokines (IL-10), but cortisol seemed to play a complicated role in halting the acute inflammatory response.
Abstract: AIMS: To elucidate bone mineral density (BMD) and bone turnover in an un-selected group of patients with Systemic Sclerosis (SSc) in national based registry. MATERIAL AND METHODS: All patients who have been diagnosed with SSc in Iceland were invited to participate in the study. Participants underwent standardized interview and delivered urine and blood samples for measurements of various bone metabolites (e.g. PTH, osteocalcin, Cross Laps, PINP, IGF-1, Cystatin-C and 25-OH-vitamin-D), before they underwent measurement of BMD with DEXA (QDR 4500 Elite). RESULTS: Twenty-four individuals, 20 female and four male, of 29 diagnosed patients with SSc in Iceland accepted to participate in the study (83%). The mean age was 60 +/- 15 years. Seventeen of 20 females were postmenopausal. Twelve patients had history of fractures. Only four patients were on treatment with bisphosphonate. All measured bone metabolites were in normal ranges, but U-calcium was in the lower ranges. According to DEXA, eight patients had osteopenia (T-value = -1.0 - -2.5) and three osteoporosis (T-value <---2.5), while six patients had BMD more than one standard deviation below the mean of age matched controls. CONCLUSION: Although the majority of patients with SSc have normal bone turnover and BMD, every fourth patient may have low BMD. No single pathogenic factor was observed, however, several individuals are in calcium saving stages reflected in low urinary calcium excretion. This may be result of defects in intestinal absorption of calcium due to gastrointestinal involvement of the disease. This study does not give opportunity to evaluate effects of treatment on BMD in this group of patients. Thus, individual evaluation concerning osteoporosis is recommended in patients with SSc.
Abstract: STUDY OBJECTIVE: The Icelandic Sarcoidosis Study (ISS) contains all tissue-verified cases of sarcoidosis in Iceland since 1981. The present study has extended registration and verification to the start of 2004, thus covering over 23 years and a total of 234 cases. The aim of this study was to elucidate the prevalence, clinical manifestation and long-term prognosis of sarcoid arthritis in this unselected nationwide cohort. The presence of joint or muscle symptoms was registered in 20% of these cases. METHODS: We used a questionnaire to register the lung and joint symptoms and all participants were offered a clinical evaluation with standardized interview and physical examination, including a count of the number of painful and/or inflamed joints. RESULTS: Forty-seven (20%) of the 234 individuals in the ISS reported skeletal symptoms. In thirty-nine cases (17%) it was possible to confirm a history of inflammatory joint disorder. The mean age was 45 years: women 46 years (30-66), men 43 years (28-66). In 82% of the cases one or both ankles were involved. In 22 or 56% of the cases (13 female and 9 male) reliable data on the disease course were obtained; 87% of the patients had full recovery in less than 6 months, while 13% of the patients (all female) experienced chronic arthritic disease. CONCLUSIONS: Our nationwide-based data confirmed that around a fifth of all those diagnosed with sarcoidosis will develop joint symptoms associated with their sarcoidosis, most usually in the ankle. The prognosis is favourable, but a subgroup of female patients may develop chronic polyarthritis. It is urgent to study further in detail the risk factors for a chronic arthritic condition in sarcoidosis; thus, it would be possible to offer those at risk of arthritis modifying anti-rheumatic treatment in the early phase of their disease course.
Abstract: OBJECTIVES: To investigate whether concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in aspirated synovial fluid can be used to distinguish rheumatoid arthritis from other forms of inflammatory arthritis. METHODS: bFGF and VEGF concentrations were measured in aspirated synovial fluid and serum samples from 66 patients with active arthritis (clinical diagnoses: rheumatoid arthritis (35 patients), psoriatic arthritis (9), reactive arthritis (11) and arthritis UNS (11)) utilizing commercial ELISA kits. RESULTS: In comparison with controls, elevated concentrations of VEGF were found in synovial fluid compared with in serum in all forms of arthritis. There were no significant differences in synovial fluid bFGF or VEGF concentrations between rheumatoid arthritis and the other forms of inflammatory arthritis. CONCLUSION: Both serum bFGF and VEGF concentrations were increased in patients with rheumatoid arthritis. Patients treated with steroids had lower synovial fluid bFGF concentrations. Synovial fluid levels of bFGF and VEGF were elevated but could not be used to distinguish rheumatoid arthritis from other forms of inflammatory arthritis.
Abstract: BACKGROUND: The use of oral corticosteroids (CS) is one of the most common causes of iatrogenic osteoporosis. Recently, therapeutic guidelines dealing with the skeletal complication of CS have been published. OBJECTIVE: To evaluate how CS are used in the community and the frequency of active intervention against corticosteroid induced osteoporosis in daily clinical practice. MATERIAL AND METHODS: After approval by the Committee on Medical Ethics and the Data Protection Commission all prescriptions for CS which were filled by pharmacies in the northeast area of Iceland (population 26,664) during a two year period were collected. Thereafter, clinical information was obtained from medical records at the healthcare centres and from the local hospital. Patients who were taking CS for at least three months a year or for repeated periods (for a total of three months annually) were included in the study. These patients also received a questionnaire about hormone replacement therapy, bisphosphonates, and dietary consumption of calcium and vitamin D. RESULTS: A total of 191 patients were included in the study or 0.7% of the population. Their mean age was 66 years (17-93) and 106/191 (55%) were women. Only 63 (33%) patients had no registered complication due to the treatment, according their medical records. Thirty nine (20%) patients had had an osteoporosis related fracture and 50 (26%) of the patients had presumed CS induced osteoporosis. A total of 52% patients were receiving supplementary vitamin D (fish liver oil) and 37% were taking calcium tablets regularly, while 91% of the patient group were consuming milk products regularly. Only 17 (9%) patients were taking bisphosphonates and 18/81 (22%) of the postmenopausal women were receiving hormone replacement therapy. CONCLUSIONS: Relatively few patients receiving long term treatment with CS are also receiving primary prevention against CS induced osteoporosis, although several patients are taking vitamin D and calcium tablets. Specific treatment against osteoporosis was in most cases instituted secondary to osteoporotic complications. Thus although there are available treatment alternatives against CS induced osteoporosis, the doctors who prescribed CS did not make use of this form of treatment for their patients.
Abstract: OBJECTIVE: To assess the prevalence of subjective sleeping complaints by patients with systemic lupus erythematosus (SLE) and to evaluate the correlation between various sleeping complaints and disease activity. METHODS: A standardised sleep questionnaire, The Uppsala Sleep Inventory, was used to investigate the sleeping habits of 30 outpatients with systemic lupus erythematosus (SLE) in comparison to population-based age- and sex-matched controls. RESULTS: Sleep deficit (difference between need of sleep and actual sleeping time) was similar in patients with SLE (0.8 +/- 0.9 hour) and age-matched female controls (0.4 +/- 0.8 hour). However, patients with SLE reported more frequent disturbances due to pain, both when trying to fall asleep (p < 0.01) and during the night (p < 0.01). They also reported frequent awakenings due to headache (p < 0.01) and disturbances due to other vegetative symptoms. Furthermore, the SLE patients were awake for significantly longer periods during the night and they estimated their degree of fatigue as significantly higher than the female controls (p < 0.0001). CONCLUSION: Patients with SLE seem to get a fairly normal amount of sleep, but are frequently disturbed by pain and by various vegetative symptoms, e.g. breathlessness, sweating, and palpitation, which indicate not only pain but also possible involvement of the nervous system. The nervous system may therefore play a role in sleep disturbances reported by patients with SLE.
Abstract: The present study aimed to compare the cellular pattern and structural changes in the airways of patients with primary Sjögren's syndrome (pSS) with healthy controls. Bronchial biopsy specimens were obtained from seven subjects with pSS and seven healthy controls. All the patients with pSS had increased bronchial responsiveness to methacholine. In the biopsies inflammatory cells, cytokine-producing cells, tenascin and laminin were visual zed by immunostaining. Patients with pSS had a higher number of neutrophils and mast cells than healthy controls, while the number of eosinophils was similar in the two groups. The number of IL-8-positive cells was higher in pSS butthe numbers of IL-4-and IL-5-positive cells were not significantly different between pSS and healthy controls. The numbers of T cells in patients with pSS were higher than in healthy controls, while the numbers of CD25-positive cells were similar to the healthy controls. The degree of epithelial integrity in patients with pSS was significantly lower than in the control group and the tenascin and laminin layers were significantly thicker in the pSS group. There was a correlation between the number of mast cells and the thickness of the tenascin and laminin layers in pSS. In conclusion, we found that the cellular pattern in the bronchial mucosa of patients with pSS displayed large numbers of neutrophils, mast cells and T-lymphocytes. These changes in inflammatory cell numbers seemed to relate to the observed increased epithelial damage and structural changes of the subepithelium. The structural findings, but not the pattern of inflammatory cells, are shared with atopic asthma and may relate to the increased bronchial hyper-responsiveness seen in both diseases.
Abstract: OBJECTIVE: To examine the degree of anxiety and depression and to assess well being and general symptoms in patients with primary Sjögren's syndrome (SS). METHODS: A standardized questionnaire, the Hospital Anxiety and Depression Scale, was used to examine the degree of anxiety and depression in patients with primary SS (n = 62) and in age matched healthy female controls. The Gothenburg quality of life instrument (GQOL) was used to assess well being and general symptoms. Patients with rheumatoid arthritis (RA; n = 38) were used as patient controls. RESULTS: The patients with primary SS had significantly higher scoring rate for "possible" clinical anxiety (48%) and for "possible" clinical depression (32%) compared with reference groups (p<0.05). The physical and mental well being of the patients with primary SS were significantly reduced compared with controls. Furthermore, patients with primary SS complained more commonly of low mood, irritability, headache, gastrointestinal symptoms, and impaired concentration and memory than the patients with RA. CONCLUSION: The results indicate that patients with primary SS often have psychiatric symptoms and worse well being, which may affect their quality of life.
Abstract: OBJECTIVES: To evaluate quality of life and psychological symptoms in patients with primary Sjögren's syndrome and to compare this with patients with rheumatoid arthritis. METHODS: A standardised questionnaire, the Psychological General Well-Being Index (PGWB), was used to examine the quality of life and psychological symptoms in patients with primary Sjögren's syndrome (pSS; n = 34). Patients with rheumatoid arthritis (RA; n = 32) were used as patient controls. RESULTS: The total mean score +/- SD for PGWB was 84.9 +/- 16.2 in pSS patients and significantly lower (p = 0.001) than in RA patients (97.7 +/- 17.5). Patients with pSS had an increased propensity for depressed mood (p = 0.0009), and suffered from reduced well-being (p = 0.002) and impaired vitality (p = 0.003). CONCLUSION: The results suggest that patients with pSS have a reduced quality of life, a higher degree of distress and a lower sense of well-being than patients with RA.
Abstract: OBJECTIVE: To study the sleep pattern in ankylosing spondylitis, and to investigate gender differences in sleep, pain, and fatigue. METHODS: Forty-three male and 27 female patients with ankylosing spondylitis completed a sleep questionnaire and the results were compared with earlier findings in 3,558 persons randomly selected from the general population. RESULTS: Too little sleep was reported by 80.8% of the female and 50.0% of the male patients, compared to 28.8% and 21.8% respectively in the reference group (p<0.0001). The main reason was pain in the pre-sleep and sleep-periods (p<0.0001). Daytime fatigue was a major problem (p<0.0001). Higher correlation was found between pain and daytime fatigue than between sleep disturbance and daytime fatigue. CONCLUSION: Sleep disturbance is a significant problem in ankylosing spondylitis. The disturbance is closely related to pain at bedtime and during the night. Gender differences exist in the subjective sleep disturbance, fatigue, and pain.
Abstract: BACKGROUND: Different mechanisms may underlie bronchial hyperresponsiveness (BHR) in different diseases. The aim of this study was to investigate the bronchial responsiveness profile produced by three different challenge tests, methacholine, a direct stimulus, and two indirect stimuli, adenosine 5'-monophosphate (AMP) and cold air, in subjects with asthma and patients with Sjögren's syndrome. METHODS: The study population comprised 40 adult patients with asthma, 18 subjects with Sjögren's syndrome, and 20 controls. Blood samples were collected before each challenge for measurements of serum eosinophil peroxidase (S-EPO) and eosinophil cationic protein (S-ECP). The investigated subjects recorded peak expiratory flow and kept a symptom diary. RESULTS: Atopic subjects with asthma were significantly more hyperresponsive to AMP than nonatopic subjects with asthma (P=0.01) and subjects with Sjögren's syndrome (P=0.02). No difference was seen between atopic and nonatopic subjects with asthma in the case of challenges with methacholine or cold air. In atopic subjects with asthma, a significant correlation was found between challenges with methacholine and AMP (r=0.91, P=0.0001) and methacholine and cold air (r=0.83, P=0.004), but, in nonatopic subjects with asthma, no significant correlation was seen between methacholine and AMP or cold air challenges. In atopic subjects with asthma, the dose-response slope for AMP was correlated to S-EPO (r= -0.56; P = 0.01) and S-ECP (r= -0.51, P = 0.02), while no correlation between BHR and inflammation markers was found in the two other patient groups. CONCLUSIONS: The results of this study suggest that patients with asthma and subjects with Sjögren's syndrome display different bronchial responsiveness profiles for different challenge agents. Atopic subjects with asthma are more hyperresponsive to AMP than nonatopic subjects and patients with Sjögren's syndrome. More than one challenge may be required to detect different aspects of bronchial responsiveness.
Abstract: Nitric oxide has an important role in the regulation of airway function and can have pro-inflammatory effects. Bronchial hyperresponsiveness (BHR) and respiratory symptoms are common in patients with Sjögren's syndrome (SS). The aim of this study was to determine whether patients with SS have an increased amount of exhaled NO and whether this NO correlates with respiratory symptoms and BHR. Exhaled NO was measured in 18 patients with SS and 13 normal subjects on three different occasions with intervals of at least 3 days using a chemiluminescence method. Airway responsiveness was assessed with methacholine provocation. Serum levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) were measured. Exhaled NO was significantly higher in patients with SS than in controls (147+/-82 versus 88+/-52 nL x min(-1); mean+/-SD; p=0.041). Exhaled NO was correlated with age (partial r=0.52, p=0.006) and serum HNL (partial r=0.46, p=0.014). There were no significant correlations between exhaled NO and respiratory symptoms, BHR or serum MPO, ECP or EPO. Disease duration was negatively associated with serum MPO (r=-0.47, p=0.043). In patients with SS, a positive correlation was found between symptom score and serum ECP (partial r=0.65, p=0.003) and EPO (partial r=0.62, p=0.004) and a negative correlation with age (partial r=-0.60, p=0.005). In conclusion, elevated levels of exhaled nitric oxide in patients with Sjögren's syndrome were demonstrated. The mechanism underlying this increase in exhaled nitric oxide in Sjögren's syndrome is not known.
Abstract: OBJECTIVE: Estimate the contribution of monocytes/macrophages to the disease process in rheumatoid arthritis (RA), by measuring the serum levels of the leucocyte-derived granular proteins: lysozyme, myeloperoxidase (MPO), lactoferrin and human neutrophil lipocalin (HNL). METHODS: Serum levels of these granular proteins were measured in patients with RA (n=23) and in healthy controls (n=27), and in 10 patients with RA after treatment with low-dose prednisolone. The serum levels of the granular proteins were also measured before and after treatment with metyrapone, a substance that inhibits the synthesis of cortisol in the adrenals. RESULTS: The serum levels of lysozyme and MPO were elevated in patients with RA, while the concentrations of lactoferrin and HNL were similar in both groups. Prednisolone treatment decreased the serum concentration of lysozyme and MPO. Metyrapone did not influence the level of the granular proteins measured. CONCLUSIONS: The increased serum levels of lysozyme and MPO, but not of HNL and lactoferrin in RA could indicate a stimulated secretory activity of mononuclear phagocytes. The measurement of serum lysozyme, as an indicator of monocyte/macrophage activity, might be used to study disease activity in RA.
Abstract: OBJECTIVE: To study granulocyte adhesion to E-selectin, VCAM-1 and ICAM-1 in patients with primary Sjögren's syndrome (pSS). In previous studies diminished neutrophil adhesion has been shown as measured by the nylon fiber method. METHODS: Neutrophil and eosinophil adhesion to the adhesion molecules E-selectin, VCAM-1 and ICAM-1 were measured using transfected fibroblasts. The cell surface expression of the integrin proteins CD11a, CD11b, CD18 and CD29 on neutrophils was assayed by means of flow cytometry. RESULTS: Neutrophils and eosinophils from patients with pSS had elevated basal adhesion in the presence of Mn2+ as compared with controls (basal adhesion was considered to be the adhesion to untransfected fibroblasts). Granulocyte adhesion to E-selectin was also elevated. No differences were seen between patients and controls in cell surface expression of the integrin proteins CD11a, CD11b, CD18 and CD29 on neutrophils, nor was there any difference in these parameters between patients with and without extra glandular symptoms. CONCLUSIONS: These results suggest that blood neutrophils and eosinophils are activated in pSS. Accordingly they do not confirm results from earlier studies of impaired neutrophil adhesion in pSS.
Abstract: The acute phase reaction is an unspecific response to inflammatory stimuli characterized by alterations in the concentration of several plasma proteins. It is of great clinical value to monitor the inflammatory state in patients with rheumatoid arthritis. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are the assays most widely used to measure the acute phase response, but there are also several other inflammatory markers (e.g., fibrinogen, haptoglobin, alpha 1-acid glycoprotein, alpha 1-antitrypsin, interleukins (IL), serum amyloid component A (SAA)). We have studied the interrelationships between several of these markers (ESR, Haptoglobin, Fibrinogen, CRP, SAA and IL-6) in rheumatoid arthritis patients. There was a good correlation between all acute phase markers in serum (p < .01). We found especially strong correlations between S-CRP and SAA (p < .000001) and between ESR and P-fibrinogen (p = .000004). The strong correlation indicates that P-fibrinogen could be used instead of ESR in monitoring rheumatoid arthritis patients. This would increase the specificity of the examination as ESR may be influenced by several factors other than the inflammatory response. There were no significant correlations between acute phase markers in serum or plasma and clinical index.
Abstract: OBJECTIVE: To test the hypothesis that the timing of prednisolone administration might be critical in determining its effect on the diurnal rheumatoid inflammatory process. METHODS: 26 patients with rheumatoid arthritis were randomly divided into two equal groups and allocated to low doses of prednisolone at either 2.00 am or 7.30 am. Because of the diurnal variation in disease activity in rheumatoid arthritis, assessments of the two study groups were performed at 7.30 am both at the start of the study (day 1) and after four doses of prednisolone (day 5). The study protocol differences in the time period from the last dose of prednisolone to assessment were 5.5 hours in the 2.00 am group and 24 hours in the 7.30 am group. RESULTS: Administration of low doses of prednisolone (5 or 7.5 mg daily) at 2.00 am had favourable effects on the duration of morning stiffness (P < < 0.001), joint pain (P < 0.001), Lansbury index (P < < 0.001), Ritchie index (P < < 0.001), and morning serum concentrations of IL-6 (P < 0.01). The other study group showed minor but significant effects on morning stiffness (P < 0.05) and circulating concentrations of IL-6 (P < 0.05). Modest and similar improvements of C reactive protein, serum amyloid protein A, and erythrocyte sedimentation rate were seen in both study groups. CONCLUSIONS: Administration of low doses of glucocorticoids with a rather short biological half life seems to improve acute rheumatoid arthritis symptoms if it precedes the period of circadian flare in inflammatory activity, as defined by enhanced IL-6 synthesis. Further studies are needed to test the relative merits of different timing protocols of glucocorticoid administration in rheumatoid arthritis.
Abstract: Bronchial hyperreactivity (BHR) is found in Sjögren's syndrome, as in a number of other conditions such as asthma. BHR associated with asthma can be effectively treated with corticosteroids or sodium cromoglycate. We treated 19 Sjögren's syndrome patients with BHR with inhaled budesonide and inhaled cromoglycate for 6 weeks each. None of the treatment had any significant effect on symptoms of hyperreactivity or lung function. There was no effect on BHR measured as methacholine reactivity. Primary Sjögren's syndrome is a disease with inflammation not only in the salivary and lacrimal glands but also in the pulmonary alveoli and the bronchi. The main inflammatory cell is the lymphocyte, whereas, in the bronchi in asthma, the eosinophil granulocyte is the characteristic inflammatory cell. The cause of the discrepancy with regard to treatability of BHR in asthma and in Sjögren's syndrome is not known. Possibly not all BHR is caused by inflammation. There is not a perfect correlation between inflammation and hyperreactivity even in asthma. Even in the bronchial inflammation and the asthma symptoms are easy to treat with anti-inflammatory medicines, a considerable component of BHR usually still remains, as measured with methacholine or histamine.
Abstract: OBJECTIVE. To study the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis (RA) and the influence of glucocorticoid treatment. METHODS. Consecutive untreated patients with RA with moderately high inflammatory activity were studied and compared with healthy subjects of similar age. Subjects were studied both at baseline and after multiple releasing hormone (MRH) stimulations. Patients were reexamined one week after starting prednisolone. RESULTS. The baseline cortisol/adrenocorticotropic hormone (ACTH) ratio was significantly lower in patients with RA. After corticotropin releasing hormone (CRH) stimulation, their serum cortisol response was reduced during the later test phases in spite of intact ACTH response. The baseline and stimulated levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) were normal. An impaired prolactin response was seen after MRH stimulation. After one week of prednisolone therapy the absolute response of serum cortisol to CRH was decreased and the stimulated prolactin response was normalized. CONCLUSION. Impaired cortisol secretion in patients with RA in the presence of intact ACTH secretion is consistent with relative adrenal glucocorticoid insufficiency. Adrenal impairment may be secondary to the inflammatory disease process.
Abstract: OBJECTIVE. To elucidate the possible development of Sjögren's syndrome in young women with previous postpartum thyroiditis, a clinical and laboratory case-control followup study was undertaken. METHODS. Forty female patients (mean age 36 years) with well documented postpartum thyroiditis 5 years previously and 30 healthy mothers (mean age 36 years) who all had undergone normal partus an average of 5 years previously, were included in the study. RESULTS. Symptoms of dry eyes, caries, arthralgias, swollen joints and fatigue were reported significantly more often in women with previous postpartum thyroiditis compared with healthy mothers of the same age (p < 0.05). Using an ELISA with purified (SSA)Ro and (SSB)La proteins derived from a human cell line as antigens, 34% of the women were anti-SSB positive and 46% were anti-SSA positive at followup. Furthermore, 15/35 women with a history of postpartum thyroiditis (43%) had objectively impaired tear and/or saliva production; 5 of 24 investigated women had keratoconjunctivitis sicca (KCS) and 2 of 7 salivary gland biopsies showed chronic lymphocytic sialadenitis. Three women (8.6%) had the combination of KCS and xerostomia. CONCLUSION. Laboratory and clinical features of Sjögren's syndrome are frequently seen in younger women with previous postpartum thyroiditis.
Abstract: OBJECTIVES--Attempts to differentiate between the pathogenesis of the severe pulmonary manifestations observed in systemic sclerosis (SSc) and the mild form in primary Sjögren's syndrome (pSS) were performed by studying cell populations recovered during bronchoalveolar lavage (BAL). METHODS AND RESULTS--Two-colour flow cytometric analysis of BAL fluid lymphocytes showed a similar degree of phenotypic activation (DR+) of CD4+ and CD8+ T lymphocyte subsets and CD16+ NK cells in patients with SSc (n = 13) and pSS (n = 11) groups and healthy controls (n = 11). Alveolar macrophages expressed the CD14 antigen at significantly increased densities in patients with SSc. Alveolar macrophage activation in SSc was also suggested by increased IL-6 concentrations in neat BAL fluid and increases in macrophage production of TNF alpha and EGF in vitro. SSc patients also had increased proportions of neutrophils and eosinophils in BAL fluid. No correlations were found between any cellular subsets or cytokine levels in BAL fluid and lung status at the time of lavage in SSc or pSS patients or the subsequent course of the pulmonary function in SSc patients. CONCLUSION--It is concluded that the phenotypical activation of alveolar helper/inducer (DR+CD4+) and suppressor/cytotoxic (DR+CD8+) T lymphocytes and NK (DR+CD16+) cells is not a prerequisite for the development of lung fibrosis in SSc or bronchial hyper-responsiveness in pSS. Alveolar macrophage activation may contribute to the development of lung fibrosis in SSc.
Abstract: OBJECTIVES--To test the hypothesis of a diurnal variation in circulating levels of interleukin-6 (IL-6) and/or tumour necrosis factor-alpha (TNF-alpha) in rheumatoid arthritis and other inflammatory connective tissue diseases. METHODS--Serum levels of IL-6 and TNF-alpha were measured at three hour intervals from 7:30 to 22:30 in 48 patients with different rheumatic diseases as well as ten healthy controls. In four of the patients with rheumatoid arthritis, serum IL-6 levels were measured before and after one week of treatment with prednisolone 15-20 mg daily. RESULTS--IL-6 and TNF-alpha could not be detected in serum from healthy controls. However, serum IL-6 levels were substantially increased in patients with rheumatoid arthritis. Furthermore, patients with rheumatoid arthritis showed a statistically significant circadian variation in levels of IL-6. Peak values appeared in the morning and low values in the afternoon and evening. In contrast, levels were low and stable in other connective tissue diseases. Levels of TNF-alpha were low in patients with rheumatoid arthritis and high in patients with other connective tissue diseases, but without circadian rhythm. After treatment with prednisolone, levels of serum IL-6 decreased significantly, but the circadian rhythm remained. CONCLUSIONS--The circadian rhythm of circulating IL-6 might correspond to the circadian rhythm of symptoms in rheumatoid arthritis. The diurnal variation of IL-6, and possibly other cytokines, might explain the conflicting results previously reported on the inter-relationship between circulating IL-6 levels and disease activity in rheumatoid arthritis.
Abstract: A standardized sleep questionnaire was used to investigate the sleeping habits of outpatients with primary Sjögren's syndrome (pSS) (n = 40) and RA (n = 42). Sleep deficit (difference between need of sleep and actual sleeping time) was significantly higher in patients with pSS when compared with healthy matched controls (P < 0.0001), and with patients suffering from RA (P < 0.001). When trying to fall asleep, patients with pSS were significantly more often disturbed by muscular tension (45%) and restless legs (24%), than patients with RA (12%, P < 0.01 and 2%, P < 0.01), and they were also significantly more troubled by nocturnal pain than patients with RA (P < 0.01). The pSS group reported significantly more disturbing by awakening during the night and was awake for longer periods than the RA group. Fatigue was a significantly more frequent complaint in patients with pSS. Polysomnography showed that all recorded patients (n = 10) had some sleep disturbances; reduced sleep efficiency (n = 8), increased number of awakenings (n = 5) and increased wakefulness surrounded by sleep (n = 9). Five patients had alpha intrusion in their sleep EEGs. The sleep disturbances seen in patients with primary Sjögren's syndrome may contribute to the fatigue associated with this disease.
Abstract: The question of whether there is a preferential use of certain V genes in T cells entering an inflamed joint has hitherto been studied mainly using unfractionated cells from synovial fluid and tissue respectively, and no clear answer to the question has yet been provided. Concomitantly, evidence has been provided that the use of V genes may differ considerably between CD4+ and CD8+ T cells, and consequently that detection of biased V-gene expression within an inflammatory lesion may require separate analysis of the two T-cell subsets. In this paper we have therefore studied T-cell receptor V-gene expression in rheumatoid arthritis by means of double stainings of synovial fluid and blood for available anti-TCR monoclonal antibodies and antibodies to CD4 and CD8, respectively. Double stainings were also performed with anti-TCR antibodies and antibodies to activation markers HLA-DR and IL-2R. A certain bias towards the preferential use of certain V genes was seen particularly in the synovial fluid samples within both the CD4+ and CD8+ T-cell populations, but no uniform pattern was evident among the 35 patients investigated.
Abstract: Eleven patients with chronic inflammatory arthritides and haemoglobin concentrations less than 105 g/l with symptoms from their anaemia were treated with a dose of 250 IU/kg/week of recombinant human erythropoietin for six weeks. The treatment was given as subcutaneous injections five days a week. All patients had active inflammatory disease. Nine patients responded to treatment with an increase in haemoglobin of more than 15 g/l. The mean (SD) haemoglobin concentration increased from 93.0 (8.0) g/l before treatment to 115.0 (12.0) g/l after six weeks. There was no correlation between the initial serum concentration of erythropoietin and the response. It was concluded that anaemia in chronic inflammatory arthritides responds to treatment with subcutaneous injections of recombinant human erythropoietin.
Abstract: The prevalence of bronchial hyperresponsiveness (BHR) to methacholine inhalation in a consecutive series of 21 patients with primary Sjögren's syndrome was studied prospectively. Slight to severe BHR was seen in 12/20 (60%) of the patients. Ten of 12 patients with BHR (83%) had a non-productive cough, wheezing, or intermittent breathlessness. Bronchial hyperresponsiveness was more common in patients with extraglandular symptoms (10/14, 71%) than in those with only glandular symptoms (29%). Spirometrically 29% (6/21) of the patients had 'small airways' disease', and all those had BHR. Of 6/21 (29%) who had diffuse interstitial lung disease, two had BHR. Three of the four patients with obstructive lung function were challenged with methacholine and two of them had BHR. Only two patients with BHR had normal spirometry findings. The data showed that respiratory disease--mostly mild or moderate but even severe bronchial hyperresponsiveness--is commonly seen in patients with primary Sjögren's syndrome.
Abstract: As nucleotide catabolism increases during tissue injury the appearance of purine metabolites in inflamed synovial fluid might be of value in understanding the joint damage in inflammatory arthritides. In this study, therefore, synovial and plasma concentrations of hypoxanthine, xanthine, and urate in 16 patients with rheumatoid arthritis (three with psoriatic arthropathy) were analysed. It was found that their plasma concentrations of hypoxanthine were greater than those of a reference group of healthy subjects. The synovial fluid concentrations of hypoxanthine, xanthine, and urate were higher than corresponding concentrations in plasma. Positive correlations were found between the respective plasma and synovial fluid values of xanthine and urate. These findings indicate a local enhanced purine metabolism in inflamed joint tissue and diffusion of oxypurines from joint cavity to plasma. No relation was found between measured metabolites and disease duration, radiological joint findings, or synovial fluid cells. Except for a weak correlation between plasma urate and serum haptoglobin, measured purine metabolites were not related to laboratory measures of systemic inflammation.
Abstract: The function of neutrophils was studied in 23 consecutive patients with primary Sjögren's syndrome and in 35 healthy controls. Nineteen patients (83%) had extraglandular symptoms and nine patients (39%) had recurrent bacterial infections. The patients had a marked reduction of neutrophil adherence, especially those with recurrent bacterial infections, and reduced opsonic activity of plasma. Increased random migration of isolated neutrophils was found in the patients with a propensity for bacterial infections. Chemotaxis and chemokinesis, phagocytosis, chemiluminescence production, and the intracellular neutrophil contents of lactoferrin and lysozyme were normal. The various aspects of neutrophil function tested in this study were not related to disease duration or to inflammatory disease activity. The impaired neutrophil adherence may play a part in the increased propensity for bacterial infections seen in patients with primary Sjögren's syndrome.
Abstract: The possible role of the eosinophil and its cytotoxic granule proteins in the vascular lesions seen in temporal arteritis was elucidated. Sixteen sections of biopsy specimens from arteria temporalis showing giant cell arteritis were stained for eosinophil cationic protein (ECP) by polyclonal antibodies and the immunoperoxidase method. Activated eosinophils were identified by monoclonal antibodies linked to alkaline phosphatase. Activated eosinophils and secreted ECP were seen in all layers of the inflamed vessels and were most evident in necrotic lesions and thrombi. Only a small number of granulocytes seen in the adventitia were immunoreactive for cathepsin G, and no extracellular deposits of this neutrophil granule protein were seen. A few immunoreactive eosinophils were found in the adventitia in two of five negative temporal artery biopsy specimens from patients with polymyalgia rheumatica. All eight coronary artery biopsy specimens with atherosclerotic lesions showed no activated eosinophils or secreted ECP. These findings indicate that eosinophils are involved in the vascular lesion in temporal arteritis and suggest that cytotoxic eosinophil granule proteins may contribute to the necrotic lesions and the development of thrombi.
Abstract: A 31-year-old white woman with biopsy verified cutaneous polyarteritis nodosa diagnosed in 1981, developed 6 years later recurrent abdominal pains, rectal bleeding and weight loss. Barium enema demonstrated typical changes of Crohn's disease with fistula in the terminal ileum. Her resected ileum showed granulomatous transmural ileitis without vasculitis. Only corticosteroids and cyclophosphamide controlled the cutaneous and the gastrointestinal symptoms until she was treated with sulfasalazine. The association between cutaneous polyarteritis nodosa and Crohn's disease is discussed and the treatment of earlier reported cases is reviewed.
Abstract: A 51-year-old housewife, who had been on treatment with amiodarone for ten months, developed a painful enlargement of the thyroid gland. Thyroid antibody titers were highly elevated and a fine needle aspirate of the gland showed infiltration of lymphocytes and plasma cells. Initially the patient was hyperthyroid, later she developed hyperthyroidism which required thyroid substitution. The possibility of amiodarone provoking autoimmune thyroiditis is discussed.
