Calprotectin (S100A8/A9) and S100A12 are associated with measures of disease activity in a longitudinal study of patients with rheumatoid arthritis treated with infliximab.

OBJECTIVES: The pro-inflammatory proteins calprotectin (a heterocomplex of S100A8/A9) and S100A12 have been associated with disease activity in rheumatoid arthritis (RA). The aim of this study was to compare their potential as biomarkers in a prospective study of RA patients starting with infliximab as their first biological disease-modifying anti-rheumatic drug (DMARD). METHOD: Thirty-nine RA patients were examined and serum samples collected when starting with infliximab and after 3, 6, and 12 months. Calprotectin and S100A12 were analysed by enzyme-linked immunosorbent assays (ELISAs) and, together with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), measured at all time points. A disease activity score of 28 joints (DAS28) was calculated. Radiographs of the hands, wrists, and feet were taken at baseline and after 3 years, and assessed according to the modified Sharp/van der Heijde (SvH) score. Responsiveness was evaluated according to the European League of Associations for Rheumatology (EULAR) response criteria based on 28 joints. RESULTS: Both S100 proteins were significantly higher in seropositive than in seronegative patients (p = 0.01). Calprotectin correlated significantly with CRP (ρ = 0.51-0.75), ESR (ρ = 0.32-0.52), and DAS28 (ρ = 0.32-0.62). S100A12 correlated with calprotectin (ρ = 0.62-0.77) and CRP (ρ = 0.32-0.63). The S100 proteins, and especially calprotectin (ρ = 0.23-0.39), showed weak associations with radiographic progression, unlike CRP/ESR. None of the S100 proteins could predict responsiveness. CONCLUSIONS: Calprotectin showed the strongest correlation with measures of disease activity and may be better than S100A12 when evaluating disease activity in RA patients. More extensive studies are needed to further compare the predictive value of the S100 proteins relative to radiographic progression.

Estimation of the prevalence of primary Sjögren's syndrome in two age-different community-based populations using two sets of classification criteria: the Hordaland Health Study.

OBJECTIVE: To estimate the point prevalence of primary Sjögren's syndrome (pSS) in two populations, aged 40-44 and 71-74 years, using two sets of classification criteria. METHODS: The participating individuals were recruited from the Hordaland Health Study (HUSK) conducted during 1997-99. A total of 18 592 individuals born 1953-57 and 3346 individuals born 1925-27 were sent a questionnaire covering various health-related questions, including four questions about sicca symptoms. Among those answering positive to at least one of the four questions, 99 and 90 individuals born 1953-57 and 1925-27, respectively, were examined further. For diagnosis of pSS two classifications were used, the preliminary European criteria from 1993, and the revised European criteria from 1996. RESULTS: By using the two classification criteria from 1993 and 1996, the point prevalences were 0.44% [95% confidence interval (CI) 0.34-0.57] and 0.22% (95% CI 0.15-0.32), respectively, for the population group born 1953-57. The corresponding estimates were 3.39% (95% CI 2.77-4.14) and 1.40% (95% CI 1.02-1.92) for the population born 1925-27. CONCLUSION: The point prevalence of pSS was approximately seven times higher in the elderly population aged 71-74 years compared to individuals aged 40-44 years, regardless of the classification criteria used.

Increased width of the apical periodontal membrane space in endodontically treated teeth may represent favourable healing.

AIM: To examine cases showing increased width of the periodontal space (IW) at a long-term follow-up examination and to determine whether this finding could be explained by endodontic or nonendodontic factors. METHODOLOGY: A series of intraoral radiographs was obtained from 131 patients 20-27 years after root canal treatment. The same individuals had been examined 10 years earlier, and radiographs taken immediately after treatment were also available. Fourteen roots (5.6%) demonstrated increased width of the apical periodontal space at the end of the study period. These were subjected to further analysis in an attempt to disclose possible explanatory factors. RESULTS: Two of the 14 cases had reduced marginal bone levels interpreted as the origin of the IW. In three cases, overextended root filling material present 10 years earlier had disappeared and the persistent IW was interpreted as representing a remodelling process. In six cases the findings were explained as being caused by physical and anatomical factors that represented healing without complete re-formation of the apical periodontal structures, or both. Three cases were judged as unfavourable, on the basis of lacking progress in healing, unsatisfactory obturation of the apical portion of the root canal or dentine resorption close to the apical end of the root filling. CONCLUSION: Most of the 14 IW cases examined after 20-27 years could be explained by reduced marginal bone support, or by physical and anatomical factors or they might represent incomplete reformation of the typical apical morphology and were thereby recorded as favourable outcomes.

Nonsurgically retreated root filled teeth--radiographic findings after 20-27 years.

AIM: To identify periapical changes in nonsurgically retreated root-filled teeth 20-27 years after root canal treatment. METHODOLOGY: From an original material of 429 roots, retreated by undergraduate students in a teaching clinic, 112 roots in 70 individuals could be evaluated radiographically 20-27 years after treatment. The same roots had been studied 10-17 years earlier. The periapical condition was registered and compared by three observers in two series of intraoral radiographs taken 10-17 and 20-27 years after treatment. A retrospective analysis was performed to gain information about probable endodontic and nonendodontic reasons for extractions of lost roots, by evaluating their periapical status immediately after retreatment and at the 10-17-year follow-up. RESULTS: Favourable outcomes were observed in 11 roots that had radiolucencies at the 10-17-year follow-up. Eight of these roots had periapical pathosis preoperatively, five of them filled with surplus root filling material. The percentage of cases recorded as normal condition at the final follow-up was 95.5%, including five cases initially recorded with increased width of the apical periodontal space. Delayed healing as a result of surplus root filling material explained most of the cases with favourable outcome assessed many years after treatment. Twenty-eight roots were lost because of extraction during the observation period, 17 during the last 10 years. Based on status at previous follow-ups, endodontic failure seems to represent a minor reason for extraction in the material. CONCLUSION: Late periapical changes, with more successful cases, were recorded when a 10-17-year follow-up after root canal treatment was extended for another 10 years. Persistent asymptomatic periapical radiolucencies, especially those with overfill, should generally not be classified as failures, as many of them will heal after an extended observation period.

Idiopathic osteosclerosis of the jaws followed through a period of 20-27 years.

AIM: The aim of the present study was to examine the prevalence of idiopathic osteosclerosis (IO) in a baseline sample and to follow the patients through an extended period of time. METHODOLOGY: The sample consisted of 210 patients treated in a dental school and having a complete series of intraoral radiographs at the time of treatment and at a follow-up 10-17 years later. A further 10 years later, 130 patients had another follow-up. RESULTS: Sixteen of the 210 patients were found to have IO, mostly in the mandibular molar and premolar regions. Fourteen had one lesion, one had two lesions and one had three lesions. The mean age of these patients was 47 years as compared to 44 years for the rest of the patient group. No sex predilection was found. At the first follow-up, one lesion had disappeared, one had reduced in size and one new lesion appeared. At the second follow-up, eight patients with IO could be re-examined. Two lesions, unchanged at the first follow-up, had reduced in size and two new lesions appeared. In the area of the new lesions, residual roots were observed in the earlier radiographs. CONCLUSION: Our findings support the theory that IO lesions should be considered anatomical variants. In some cases, however, a local aetiological agent may cause development of structures with an identical appearance.

Periapical changes following root-canal treatment observed 20-27 years postoperatively.

AIM: The aim of the present study was to identify periapical changes 20-27 years after root-canal treatment. METHODOLOGY: The periapical condition of 265 roots filled by undergraduate students was evaluated in two series of intraoral radiographs taken 10-17 and 20-27 years after treatment. Roots (72) not recorded with a normal periapical situation on both occasions by two observers, were re-evaluated by other two examiners, separately and jointly. Final decisions about diagnoses were made by all four examiners. A strict definition was used for the identification of cases with an unfavourable outcome. RESULTS: Favourable outcomes were observed in 6.4% of the roots that had radiolucencies at the 10-17-year follow-up. Periapical radiolucencies after 20-27 years appeared in 1.5% of all other roots. The radiographic failure frequency for the total material was 4.9%. The percentage of cases with normal periapical findings at the final follow-up was 86.4%, whilst 8.7% were recorded with increased width of the apical periodontal space. Delayed healing owing to surplus root-filling material explained nearly all of the cases with favourable outcome assessed many years after treatment. CONCLUSIONS: Late periapical changes, with more successes than failures, were recorded when a 10-17-year follow-up period after root-canal treatment was extended for another 10 years.

Diagnosing periapical lesions--disagreement and borderline cases.

AIM: The aim of this paper is to present a selection of disagreement and borderline cases from a methodological study on the radiographic diagnosis of periapical disease. METHODOLOGY: Thirty-two roots, 12% of the material in an earlier study, were subjected to joint discussion because of diagnostic problems. The aim was consensus. Six cases representing different teeth/roots illustrating typical problems are presented. RESULTS: The varying morphology of apical areas and varying density of surrounding bone present a number of challenges. Even so, the joint discussion resulted in an agreement for all the cases. Twenty-five diagnoses were established and seven cases were not diagnosed owing to substandard radiographs. CONCLUSION: A detailed analysis of the periodontal ligament space, the lamina dura, trabecular pattern and bone marrow spaces is mandatory for the radiographic diagnosis of periapical disease

Long-term reliability and observer comparisons in the radiographic diagnosis of periapical disease.

AIM: The aim of this study was to evaluate and compare the long-term diagnostic consistency of two examiners, an endodontist and a radiologist, and to make comparisons with findings recorded by an observer with more recent scientific and clinical experience in endodontics. METHODOLOGY: Three groups, each consisting of 20 full mouth series of intraoral radiographs, with 79, 93 and 85 endodontically-treated roots, respectively, were successively evaluated for periapical disease. Evaluations were at first performed separately by the three observers. Disagreement and difficult, borderline cases were subjected to joint evaluation. Intra- and interexaminer comparisons were made. For two of the observers the observations were compared with findings recorded several years before for the same cases in the same radiographs. RESULTS: The intra- and interobserver long-term reliability of the two original examiners resulted in 83% overall agreement, the kappa values were 0.54, 0.57 and 0.53. Comparisons between all three observers disclosed 82%, 85% and 86% agreement and kappa values 0.55, 0.58 and 0.60. The joint evaluations and decisions did not indicate a dominating influence from any of the observers. CONCLUSIONS: The long-term reliability of the two original observers was judged as being satisfactory. All three observers judged the overall disease status of the material in the same way. The joint discussions of selected cases might reduce observer variation to an acceptable level, avoid a number of false recordings and increase the reliability and validity of the findings.

Associations of MHC class II alleles in Norwegian primary Sjögren's syndrome patients: implications for development of autoantibodies to the Ro52 autoantigen.

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by dryness of the eyes and mouth. Currently, the highly polymorphic major histocompatibility complex (MHC) genes are the best documented genetic risk factor for the development of autoimmune disease. We examined the MHC class II alleles DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 in a group of Norwegian pSS patients and compared with a group of healthy controls. Because a number of studies have shown that some of the MHC class II alleles are not associated with the disease as a whole, but rather to the development of autoantibodies, anti-Ro52 autoantibodies in serum were measured and compared to MHC class II allele status. A clear association with pSS was detected for the DRB1*0301 and DRB3*0101 alleles, but these alleles were more closely associated with the presence of anti-Ro52 autoantibodies than with pSS itself. Moreover, the DQA1*0501 and DQB1*0201 alleles were only associated with the presence of anti-Ro52 autoantibodies. This study shows that the production of anti-Ro52 autoantibodies in pSS is associated with the DRB1*0301, DRB3*0101, DQA1*0501 and DQB1*0201 alleles which are in strong linkage disequilibrium.

[Heredity and immunology in Sjogren's syndrome]. / Arvelighet og immunologi ved Sjögrens syndrom.

BACKGROUND: Over the next 3-5 years, the rapid progress in genomic research will enable the discovery of many genes associated with the more common diseases. An example of such a common disease is the rheumatic disorder Sjögren's syndrome, an autoimmune disease. A more precise genetic explanation of the mechanism leading to Sjögren's syndrome remains to be given. MATERIAL AND METHODS: One way of investigating the disease related genes in such complex polygenic diseases is to perform linkage studies in families with two or more affected. Another possibility is to conduct association studies on trios (parents and affected child), case control studies, or other experimental designs. In association studies one is testing if an allele is significantly elevated among patients compared to controls, while in linkage analyses one finds subchromosomal regions that are significantly more often inherited by patients than by healthy family members. RESULTS: The most well defined genetic association in Sjögren's syndrome is currently related to different HLA alleles and their association with anti-Ro/SSA and anti-La/SSB autoantibodies. Additional genetic studies focusing on non-HLA regions are under way. INTERPRETATION: Increased genetic knowledge would allow optimisation of the diagnostic criteria as well as development of new and more effective treatment for Sjögren's syndrome, which causes substantial suffering for a large group of patients.

Isotype distribution of anti-Ro/SS-A and anti-La/SS-B antibodies in plasma and saliva of patients with Sjögren's syndrome.

In this study an ELISA assay was used to quantify the levels of antibodies against the recombinant Ro 52 kD, Ro 60 kD, and La 48 kD proteins in plasma and saliva of 17 Sjögren's syndrome patients. The levels of total IgG, IgA, and IgM were also quantified. About one third of the patients had salivary enrichment of IgA and IgM against the Ro 52 kD, Ro 60 kD, and La 48 kD antigens and IgG against La 48 kD, while no enrichment of IgG against Ro 52 kD and Ro 60 kD was found. Most correlations between plasma and saliva levels of antigen specific antibodies were highly significant, as were most correlations between focus score and levels of antigen specific antibodies in plasma and saliva. In total, the results support the hypothesis that autoantibodies are produced in the salivary glands. The strong correlation between focus score and plasma and saliva levels of autoantibodies, indicates that the local autoantibody production is a consequence of local inflammation.

Increased frequency of cells secreting interleukin-6 and interleukin-10 in peripheral blood of patients with primary Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disease of exocrine glands. There is increasing evidence that interferon-gamma (IFN-gamma) plays a role in the pathogenesis of SS. It has also been suggested that other type 1 cytokines, as well as interleukin-6 (IL-6), IL-10 and transforming growth factor-beta, are important in the induction and/or maintenance of SS. The aim of this study was to investigate the type 1/type 2 cytokine pattern in peripheral blood of primary SS patients. The enzyme-linked immunospot (ELISPOT) assay was performed to quantify the number of mononuclear cells (MNC) secreting IFN-gamma, IL-6 and IL-10 in peripheral blood samples from 33 patients with primary SS and 12 healthy controls. The mean number of cells secreting IFN-gamma was 9/105 MNC in the SS patient group, and 4/105 MNC in the control group (P = 0.73). Fifteen of the SS patients had anti-Ro 52 kDa antibodies in serum. In this patient group the mean number of cells secreting IFN-gamma was 4/105 MNC, while in the patient group without such antibodies the mean number of cells secreting IFN-gamma was 14/105 MNC (P = 0.04). The mean number of cells secreting IL-6 was 12 000/105 MNC in the SS patient group, and 5000/105 MNC in the control group (P = 0.01). The mean number of cells secreting IL-10 was 270/105 MNC in the SS patient group, and 180/105 MNC in the control group (P = 0.04). The SS patients had a significantly higher number of cells secreting IL-6 and IL-10 in peripheral blood than the healthy controls, which may facilitate B-cell activation and production of autoantibodies.

Ro/SS-A- and La/SS-B-reactive B lymphocytes in peripheral blood of patients with Sjögren's syndrome.

The aim of this study was to investigate the production of anti-Ro/SS-A and anti-La/SS-B antibodies in peripheral blood (PB) of patients with Sjögren's syndrome (SS). The ELISPOT method was performed to quantify the frequency of PB lymphocytes spontaneously secreting anti-Ro/SS-A and/or anti-La/SS-B antibodies. The total number of IgG-, IgA- and IgM-producing cells was also quantified. The recombinant Ro 52-kD, Ro 60-kD and La 48-kD proteins were used as target antigens. Three of 18 SS patients had PB lymphocytes secreting IgG antibodies against the recombinant Ro 52-kD protein. The same three patients had high serum titres of anti-Ro 52-kD antibodies. In addition, these patients were classified as having severe disease, and all three had focus scores of >/= 8 in biopsies of the labial salivary glands (LSG). The correlation between the number of PB cells producing IgG antibodies against the recombinant Ro 52-kD protein and the focus score was significant (P < 0.01). The results indicate that only SS patients with severe disease and high degree of local inflammation in LSG have B cells producing anti-Ro/SS-A antibodies in PB. Thus, most of the spontaneous autoantibody production must take place in other body compartments, e.g. in exocrine glands and probably also in the lymphoid organs and/or other mucosal sites.

Ro/SS-A-reactive B lymphocytes in salivary glands and peripheral blood of patients with Sjögren's syndrome.

The aim of this study was to investigate the production of anti-Ro/SS-A antibodies in labial salivary glands (LSG) and peripheral blood (PB) of Sjögren's syndrome (SS) patients. The ELISPOT method was performed to quantify the frequency of LSG lymphocytes and PB lymphocytes spontaneously secreting anti-Ro/SS-A antibodies. The total number of IgG-, IgA- and IgM-producing cells was also quantified. The bovine Ro 60-kD protein was used as target antigen. Six of six primary SS patients had LSG B cells producing anti-bovine Ro 60 kD of the IgG isotype, and two of two primary SS patients had in addition PB lymphocytes producing anti-bovine Ro 60 kD of the IgG isotype. The six patients who had IgG antibodies against the Ro/SS-A antigen in LSG all had focus scores of >/= 7 in biopsies of LSG. The results indicate that SS patients with a high degree of local inflammation in LSG have B cells producing anti-Ro/SS-A antibodies in both LSG and PB. Thus, the anti-Ro/SS-A antibodies may have pathogenic importance in the progression of the exocrinopathy of SS.

Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren's syndrome.

OBJECTIVE: To investigate and identify the presence of cells producing anti-Ro/SSA and anti-La/SSB autoantibodies in salivary glands from patients with Sjögren's syndrome (SS). METHODS: Submucosal salivary gland biopsy samples from 10 SS patients (8 with and 2 without circulating Ro and La autoantibodies) and 14 control subjects were evaluated. Frozen tissue sections were immunostained by an avidin-biotin complex technique, using biotinylated recombinant Ro and La proteins as detection reagents. Autoantibody levels in SS patient sera were analyzed by enzyme-linked immunosorbent assay. RESULTS: Cells producing autoantibodies to the Ro 52-kd, Ro 60-kd, and La proteins were recorded in 8, 6, and 7 of the 10 SS patient biopsy samples, respectively. Samples from the 2 SS patients without circulating Ro and La autoantibodies were negative for these autoantibody-producing cells, as were all control biopsy samples. A strong positive correlation between the presence of autoantibodies in sera and the presence of autoantibody-producing cells in glandular biopsy tissues was evident. The number of autoantibody-producing cells and the serum autoantibody levels were also correlated (r(s)=0.94, P < 0.0001). CONCLUSION: Using a novel technique, we have demonstrated the presence of Ro and La autoantibody-producing cells in salivary gland biopsy tissues from patients with SS. These findings indicate that anti-Ro/ SSA and anti-La/SSB autoantibodies are produced and are present at sites of inflammation and indicate their potential involvement in the autoimmune exocrinopathy of this disease.

Stability after Le Fort I osteotomy in cleft lip and palate patients.

Le Fort I osteotomies were performed in 20 patients with cleft lip and palate as a one-segment movement, and the fragments were fixed with miniplates without bone grafting. Tracings of preoperative and serial postoperative lateral cephalograms were used to determine changes in maxillary position. The posterior nasal spine, not subjected to extensive changes during surgical procedures and remodeling, was found to be the most reliable landmark for measuring maxillary advancement and stability. The mean maxillary advancement was 5.96 mm. Analysis did not reveal significant changes in linear and angular measurements from immediately postoperative to 6 months postoperative. A modest maxillary advancement by Le Fort I osteotomy, along with alleviation of palatal scar tissue tension and miniplate fixation, is a stable surgical method in patients with cleft lip and palate.

Differential immunological aberrations in patients with primary and secondary Sjögren's syndrome.

The aim of the present study was to analyse possible differences in immunological features between patients with primary and secondary Sjögren's syndrome (SS). Ten patients with primary SS and 10 patients with secondary SS also suffering from rheumatoid arthritis, were identified according to established criteria for SS. Ten healthy, age-matched women served as controls. The authors analysed the phenotypic characteristics of lymphocytes in peripheral blood as well as in focal inflammatory infiltrates of minor salivary gland biopsies. Functional analyses of T lymphocytes were performed after stimulation with mitogens and antigen. B cell activity was determined at the single cell level by spontaneous and mitogen induced immunoglobulin production. Serum levels of IL-4, IL-6 and IFN-gamma were also analysed. Patients with primary SS displayed a significantly higher degree of salivary gland inflammation and reduced salivary flow than did patients with secondary SS. Decreased in vitro T cell responses to antigen and mitogens were evident in both patient groups. The CD4/CD8 ratios in both peripheral blood and salivary gland lesions were significantly lower in primary SS compared with secondary SS patients. Polyclonal B cell activation, measured as the frequency of spontaneous immunoglobulin producing cells, was most prominent in primary SS, whereas a diminished response to poke-weed mitogen (PWM), a T cell dependent B cell mitogen, was more pronounced in secondary SS. The results reveal certain immunological aberrations in the whole group of patients with SS. In addition, the authors demonstrated distinct differences in immune dysfunction between patients with primary and secondary SS, indicating that they may constitute separate entities.

Indicators of salivary gland inflammation in primary Sjogren's syndrome.

The aim of this study was to establish additional indicators in saliva and plasma which are associated with salivary gland inflammation in patients with primary Sjögren's syndrome (SS). ELISA assays were used to determine the concentrations of sICAM-1, sVCAM-1, sIL-2R alpha, IgA, IgG, calprotectin and albumin in parotid saliva, whole saliva and plasma samples. Soluble ICAM-1 was present in whole and parotid saliva samples from primary SS patients. Soluble VCAM-1 and sIL-2R alpha could not be detected in salivary samples from either primary SS or control subjects. IgA, IgG, calprotectin and albumin concentrations were higher in both whole and parotid saliva in the patient group compared with the control group. The results showed increased levels of calprotectin in all saliva samples compared to plasma, suggesting that calprotectin may be locally produced. Increased plasma values of sICAM-1, sVCAM-1, sIL-2R alpha, IgA, IgG and calprotectin were detected in primary SS patients when compared to controls. The output/min of IgA, IgG, calprotectin and albumin was decreased in SS patients. Plasma levels of various proteins could offer information concerning glandular and extraglandular inflammatory processes. However, salivary levels of these proteins (particularly sICAM-1) tend to reflect more the local inflammatory activity, providing a convenient and non-invasive tool for diagnosis.

Periapical radiolucencies as evaluated by bisecting-angle and paralleling radiographic techniques.

Two groups of patients were included in the study. The first group consisted of patients who received root canal treatment of single-rooted teeth (n = 63). The completed roof fillings were exposed to two different radiographic techniques, the paralleling and the bisecting-angle technique. The second group consisted of 1-year review radiographs of patients who had received apicectomies of single-rooted teeth (n = 105). Three observers examined the radiographic images. First, they were asked to identify teeth with a normal apical condition and those with an apical radiolucency. Thereafter pairs of radiographs were compared; cases judged as normal by all observers were excluded. The observers were now asked to ascertain whether the apical radiolucency was largest in the first image, the apical radiolucency was largest in the second picture or both radiolucencies were the same size. Both intraobserver and interobserver agreement, calculated as Cohen's kappa, was high with respect to the presence of lesions within both samples and it was at the same level for both radiographic techniques. The evaluation of the size of the lesions proved to be more inconsistent. Kappa values were in the range 0.38-0.71 for intraobserver comparisons and in the range 0.25-0.48 for interobserver comparisons. No significant difference was found between the size of lesions as recorded by the two techniques (P > 0.05). It is concluded that, when correctly adjusted the bisecting-angle technique and the paralleling technique provide similar diagnostic results.