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ID PMID Title PublicationDate abstract
14717615 Myelopathy in Sjögren's syndrome: role of nonsteroidal immunosuppressants. 2004 The incidence, aetiology and optimal treatment of CNS Sjögren's syndrome, including myelopathy associated with Sjögren's syndrome, are unknown at the present time. CNS Sjögren's syndrome is thought to be the result of an autoimmune vasculitis, but other mechanisms may be important. Spinal cord involvement in CNS Sjögren's syndrome may present as acute transverse myelitis, progressive myelitis, Brown-Séquard syndrome, neurogenic bladder or lower motor neurone disease. Optic nerve pathology frequently accompanies spinal cord involvement. Acute transverse myelitis has a high mortality and appears to be the most frequent form of spinal cord involvement in CNS Sjögren's syndrome, occurring in about 1% of all patients with Sjögren's syndrome. The patient's symptomatology and clinical course dictate current treatment of myelopathy. First-line treatment appears to be corticosteroid therapy. However, when the patient's condition fails to improve or deteriorates a nonsteroidal immunosuppressant agent should be considered. Agents used to treat myelopathy include cyclophosphamide, chlorambucil, azathioprine, ciclosporin (cyclosporin) and methotrexate in conjunction with corticosteroids. Most data exist as anecdotal reports. The agent of first choice, based on adverse effect profile and efficacy, appears to be cyclophosphamide given intravenously in pulse doses. Other nonsteroidal immunosuppressant agents should be considered, especially when lack of efficacy of, or intolerance to, cyclophosphamide exists in the patient's history. Glandular and other extraglandular symptoms may benefit concomitantly from the immunosuppressant treatment. In addition, when acute relief of symptomatology is needed, the patient may benefit from a trial of plasmapheresis or intravenous immunoglobulin. Infliximab (anti-tumour necrosis factor-alpha antibodies) has not been used as a treatment modality for myelopathy, but has shown some usefulness in the treatment of extraglandular symptoms, as well as peripheral nervous system manifestations of Sjögren's syndrome. This agent might be considered when all other treatment modalities have failed given the presumed importance of tumour necrosis factor in the pathogenesis of Sjögren's syndrome.
14672901 Fas gene promoter polymorphisms in primary Sjögren's syndrome. 2004 Jan BACKGROUND: Fas mediated apoptosis may be important in the pathogenesis of primary Sjögren's syndrome (pSS). OBJECTIVE: To examine genetic variation in the promoter region of the Fas gene in pSS. METHODS: Two single nucleotide polymorphisms at positions -1377(G/A) and -670(G/A) in the Fas gene promoter were genotyped by PCR-SSP in 101 patients with pSS and 108 Caucasoid controls. RESULTS: No significant differences in allele or genotype frequencies were detected between the patients with pSS and controls. However, significant associations were observed with Ro/La autoantibody negative patients, who display milder and later onset disease. The -670A allele was more frequent in Ro/La autoantibody negative patients than in Ro/La autoantibody positive patients (p = 0.04). CONCLUSION: This study does not confirm an earlier report of an association between pSS and the Fas promoter -670G allele. However, the results suggest that genetically determined variability in Fas expression may modulate Ro/La autoantibody responses in patients with pSS.
14531961 The genetics of primary Sjögren's syndrome. 2003 Aug Primary Sjögren's syndrome is an autoimmune disease characterized clinically by dryness of the eyes and mouth. The use of different classification criteria for primary Sjögren's syndrome has led to dramatically different estimates of prevalence and incidence. Despite this, several genetic and environmental factors are thought to play a role in the susceptibility to primary Sjögren's syndrome, as is the current conceptual formulation of the pathogenesis of many other autoimmune maladies. Primary Sjögren's syndrome appears a complicated polygenic disorder with many genes interacting with environmental factors. Similar to many other polygenic autoimmune rheumatic diseases, human leukocyte antigen associations have been reported and confirmed. Additionally, other non-human leukocyte antigen candidate genes have been reported to reveal association with primary Sjögren's syndrome, but, in general, these effects are not confirmed. The authors review the human leukocyte antigen and non-human leukocyte antigen genetic associations herewith, knowing that new technologies are providing access to the entire genome for association studies. No doubt a much more comprehensive description of the genetics of this disorder will soon emerge.
12634239 Interleukin 1beta and tumour necrosis factor alpha secreting cells are increased in the pe 2003 Apr OBJECTIVE: To study systemic alterations of cytokine secreting peripheral blood mononuclear cells (PBMC) in primary Sjögren's syndrome (pSS) and their relation to common clinical and immunological manifestations of this disease. METHODS: PBMC spontaneously secreting tumour necrosis factor alpha (TNFalpha), interleukin 1beta (IL1beta), and interleukin 6 (IL6) were assessed by enzyme linked immunospot (ELISPOT) analysis in a cohort of 31 patients with pSS fulfilling the modified European classification criteria. Nineteen healthy volunteers served as controls. ELISPOT results were correlated with glandular and extraglandular manifestations and autoantibody titres-that is, rheumatoid factor (RF) isotypes, anti-Ro/SS-A, anti-La/SS-B as determined by an enzyme linked immunosorbent assay (ELISA) technique. RESULTS: The number of TNFalpha and IL1beta secreting cells was significantly higher in patients with pSS than in controls. No differences were detected in the number of IL6 secreting PBMC. Patients with recurrent parotid swelling (RPS) had a significantly increased number of IL1beta secreting PBMC. Moreover, the number of IL1beta secreting PBMC correlated with the disease duration (r(s)=0.479; p<0.01) and with the concentration of IgM RF (r(s)=0.63; p<0.01) and IgG RF (r(s)=0.42; p<0.05). Other autoantibodies did not correlate with cytokine secreting PBMC. CONCLUSION: The increased systemic secretion of IL1beta and TNFalpha in patients with pSS points to a pathogenic impact of these cytokines in this autoimmune disease. In particular the correlation of IL1beta secreting PBMC with RPS and RF production indicates that IL1beta is a crucial regulator in the development of local and systemic disease manifestations.
12429532 Detection of maternal-fetal microchimerism in the inflammatory lesions of patients with Sj 2002 Dec BACKGROUND: A possible relation between maternal-fetal microchimerism and autoimmune diseases with some similarities to chronic graft versus host disease (cGVHD) has been reported. OBJECTIVE: To investigate whether cells with male DNA exist in female patients with Sjögren's syndrome (SS) as SS has clinical features similar to those of cGVHD. METHODS: DNA was extracted from 27 samples of peripheral blood mononuclear cells (PBMC), 42 biopsy samples of labial salivary glands (LSG), and nine samples of bronchoalveolar lavage fluid (BALF) cells from 56 female patients with SS. The presence of male DNA was determined by nested polymerase chain reaction (PCR) and by fluorescence in situ hybridisation (FISH). RESULTS: Among 56 female patients with SS, 42 patients had at least one male child. Among those 42 patients, none of the 22 PBMC but 10/28 (36%) LSG samples tested positive by PCR for the Y chromosome-specific sequence (p=0.0013). The Y chromosome-specific sequence was not detected in the samples of LSG in 10 patients without SS. In the BALF samples 2/9 (22%) patients with SS tested positive by PCR. Cells containing the Y chromosome were shown to exist in all the LSG specimens from three female patients with SS by FISH. CONCLUSIONS: Maternal-fetal microchimerism was shown for the first time to exist in the salivary glands and lungs of female patients with SS in this study. The presence of non-host cells in the inflammatory lesions but not in the peripheral blood suggests a possible role for maternal-fetal microchimerism in the pathogenesis of SS.
15576414 Changes in salivary gland immunohistology and function after rituximab monotherapy in a pa 2005 Jun OBJECTIVES: To report the successful use of rituximab on salivary gland immunohistology and function in a patient with Sjogren's syndrome (SS) and associated MALT lymphoma. CASE REPORT: The patient was a 42 year old woman with primary SS and associated MALT lymphoma located in the parotid gland and the hard palate. Four infusions of rituximab (375 mg/m(2)) weekly resulted in complete remission of the lymphoma. An incision biopsy of the parotid gland before and after treatment showed improvement of the (immuno)histopathological characteristics of SS, with possible regeneration of salivary gland tissue. Furthermore, salivary analysis showed decreased inflammatory characteristics and increased stimulated salivary flow. DISCUSSION: Rituximab is a promising agent in the treatment of SS associated MALT lymphoma. In addition to the effect on MALT lymphoma, B cell depletion by rituximab may also attenuate the activity of SS. This case report is the first to describe the effect of rituximab on histological and sialometric/chemical characteristics of SS. The efficacy of rituximab in the treatment of SS warrants further investigation.
15218897 Oral health condition and saliva flow in southern Chinese with Sjögren's syndrome. 2004 Jun OBJECTIVE: To investigate the oral health condition and saliva flow of southern Chinese patients with Sjögren's syndrome (SS). METHOD: 51 SS patients (26 primary and 25 secondary cases) and 29 controls took part in this cross-sectional study. Stimulated whole and parotid saliva flow rates, pH, and buffer capacity, and xerostomia, oral mucosal lesions, oral hygiene status, dental and periodontal conditions, prosthetic status were assessed and compared between groups. RESULTS: Stimulated whole saliva (SWS) flow was reduced in primary and secondary SS cases (p<0.001), pH and buffer capacity were also reduced in the primary SS group (p<0.05). SS patients had a greater prevalence of xerostomia than controls (p<0.001). Primary SS patients had a higher mean DMFT, more missing teeth, and more prostheses than secondary SS cases and controls (p<0.05). SWS flow correlated negatively with the number of filled teeth in both SS groups (p<0.05) and the number of decayed teeth in the primary SS group (p<0.05). CONCLUSION: Despite good oral hygiene and regular dental check-ups, the oral health of southern Chinese with primary SS was significantly compromised compared with secondary SS cases and controls, most probably due to the combined effect of impaired salivary gland function and poorer saliva buffer capacity.
14740447 Autonomic nervous system dysfunction involving the gastrointestinal and the urinary tracts 2003 Nov OBJECTIVE: Antibodies reacting with the m3 subtype muscarinic acetylcholine receptor appear to be an important pathogenic factor in primary Sjögren's syndrome (pSS). As this receptor subtype is functionally important in the gastrointestinal and urinary tracts, and very little is known about the autonomic nervous system function in these organs in pSS patients, the occurrence and clinical significance of an autonomic nervous system dysfunction involving the gastrointestinal and urinary tracts were investigated. METHODS: Data on clinical symptoms attributable to an autonomic dysfunction were collected from 51 pSS patients. Gastric emptying scintigraphy and urodynamic studies were performed on 30 and 16 patients, respectively, and the results were correlated with patient characteristics and with the presence of autonomic nervous system symptoms. RESULTS: Gastric emptying was abnormally slow in 21 of the 30 examined patients (70%). Urodynamic findings, compatible with a decreased detrusor muscle tone or contractility were found in 9 of the 16 patients tested (56%). Various symptoms of an autonomic nervous system dysfunction were reported by 2-16% of the patients. CONCLUSION: Signs of an autonomic nervous system dysfunction involving the gastrointestinal and the urinary systems can be observed in the majority of pSS patients. This high occurrence is rarely associated with clinically significant symptoms. The authors presume a role of autoantibodies reacting with the m3 muscarinic acetylcholine receptor in the elicitation of the autonomic dysfunction.
12960601 Salivary gland scintigraphy in Sjögren's syndrome: are quantitative indices the answer? 2003 Sep We evaluated the role of quantitative indices derived from dynamic 99mTc-pertechnetate salivary scintigraphy in the differentiation between a group of patients with Sjögren's syndrome (SS), a group of patients without xerostomia, but with underlying autoimmune disorders, and a group of controls. Seventeen patients with SS (group A), 18 patients with autoimmune disorders (group B) and 15 controls (group C) underwent dynamic salivary gland scintigraphy. Functional indices for the parotid and submandibular glands were calculated and comparisons were made between the groups. There were no significant differences between the three groups in terms of the maximum accumulation (MA), maximum secretion (MS) and pre-stimulatory oral index (PRI). The uptake ratios (URs) for both the right and left parotid glands and the left submandibular gland in group A were significantly lower than those in group C, but no different from those in group B. The URs for the parotid glands in group B were significantly less than those in group C. The percentage uptake by the right parotid gland at 4 min (U4) was significantly lower in group A than in groups B or C, and lower than the percentage uptake by the left parotid gland at 4 min in group A. The rest of the U4 values and all of the uptakes at 14 min (U14) were not significantly different between the three groups. The time taken for the right parotid gland to reach peak activity (Tmax) was significantly less in group A than in the other groups, but other glands showed no significant differences. It can be concluded that MA, MS and PRI cannot be used to differentiate between the three groups. The URs in groups A and B were no different, but were significantly lower than those in group C. However, the extensive overlap between xerostomic patients and normal controls for all the quantitative indices calculated imposes a severe limitation on their discriminatory power.
12666714 Analysis of in situ proliferative activity in oral gingival epithelium in patients with xe 2003 Feb BACKGROUND: Sjögren's syndrome is an autoimmune disease characterized by xerostomia and keratoconjunctivitis sicca. The relationship between xero-stomia and proliferative activity in human gingival epithelium is not known. Proliferating cell nuclear antigen (PCNA) is a nuclear protein associated with the cell cycle. Nuclear PCNA immunoreactivity is found in the proliferative compartment of normal tissues. The aims of this study were to evaluate PCNA expression in oral gingival epithelium of healthy and inflamed gingiva obtained from patients with Sjögren's syndrome, and to compare the results to age- and gender-matched subjects with normal salivary function. METHODS: Eighteen Sjögren's syndrome patients and 28 controls (14 with chronic periodontitis and 14 with no clinical evidence of periodontal disease) were included in the study. Biopsies were obtained from both inflamed and healthy gingiva. The expression of PCNA was evaluated in formalin-fixed, paraffin-embedded gingival samples using an immunoperoxidase technique and PC10 monoclonal antibody to PCNA. RESULTS: PCNA expression was observed both in the basal and suprabasal layers, and was found to be more prominent in the suprabasal layers. Proliferative index (PI) in inflamed gingiva was significantly lower in the Sjögren's syndrome group. However, no significant difference was observed between the study and control groups with respect to PI in healthy gingiva. In both groups, PI was found to be increased due to inflammation. CONCLUSIONS: Our data indicate that proliferative activity is observed in the suprabasal layers and, less frequently, in the basal layer. Inflammation caused increased proliferative activity. However, this positive effect of inflammation on epithelial cell proliferation decreased significantly with a lack of saliva. Therefore, it appears that saliva-derived biological mediators may also contribute to increased proliferative activity observed during inflammation.
12226054 The inadvisability of thoracoscopic lung biopsy on patients with pulmonary hypertension. 2002 Sep The use of video-assisted thoracoscopic surgery (VATS) sometimes leads to additional and unnecessary risks compared with thoracotomy. We report a troubling case of VATS lung biopsy in a 43-year-old woman with mild pulmonary hypertension. A progressive elevation of pulmonary artery pressure (PAP) was noted after the commencement of right unilateral ventilation. When the systolic PAP reached 90 mm Hg (390 min after induction of anesthesia), a massive blood discharge through the chest drain occurred. At repeat thoracotomy, continuous blood spouting was seen from > 10 of the surgical sites. It was supposed that the endoscopic staplers were unable to maintain hemostasis with such a high PAP.
11908561 Sicca symptoms and anti-SSA/Ro antibodies are common in mixed connective tissue disease. 2002 Mar OBJECTIVE: To examine a large well characterized cohort of patients with mixed connective tissue disease (MCTD) and determine longitudinally the prevalence of clinical and serologic features of Sjogren's syndrome in these patients. METHODS: Patients were followed longitudinally up to 30 years with systematic clinical and serologic analysis. Sera were analyzed for reactivity with SSA/Ro, SSB/La, and snRNP polypeptide U1-70kD and for anticardiolipin antibodies. RESULTS: Among a well characterized patient population with MCTD, 18/55 (32.7%) had antibodies to SSA/Ro, while 2/55 (3.6%) had antibodies to SSB/La, either initially or during the course of followup. All patients had antibodies to U1-70kD small nuclear ribonucleoprotein antigen. Sicca symptoms were common, occurring in 23/55 (41.8%) patients. Patients with MCTD who were anti-SSA/Ro positive had increased incidence of malar rash (p < 0.03) and photosensitivity (p < 0.001) compared to anti-SSA/Ro negative patients. CONCLUSION: Sicca symptoms are frequent in patients with MCTD, occurring in up to one-third of the patients studied. The presence of anti-SSA/Ro antibodies identifies a group of MCTD patients with a very high incidence of malar rash and photosensitivity.
15489070 High-resolution CT imaging of the lung for patients with primary Sjogren's syndrome. 2004 Nov PURPOSE: To assess pulmonary abnormalities in patients with primary Sjogren's syndrome (PSS) using high-resolution computed tomography (HRCT). MATERIAL AND METHODS: The HRCT scans of 24 patients with the diagnosis PSS were retrospectively reviewed regarding the presence, extension and distribution of 16 pathological findings. RESULTS: Nineteen patients (79.2%) showed pathological findings and in five patients (21.8%) the HRCT scan was judged to be normal. A predominance of abnormalities in the lower lobes and subpleural areas was detected. The following pathologies were found: bronchiectasis, thin-walled cysts and small pulmonary nodules (46.2%), ground-glass attenuation and emphysema (37.8%), interlobular-septal thickening (29.4%), honeycombing (25.2%), bronchial wall thickening, tree-in-bud pattern (21.0%), mosaic perfusion (16.8%), architectural distortion (12.6%). Airspace consolidation, air trapping, large nodules (10-30mm) and masses (>30mm), mediastinal lymph node enlargement (>15mm) and free pleural fluid were seen each in 4.2%. In 7 of the 11 patients with thin-walled cysts areas of ground-glass attenuation were detected. CONCLUSION: HRCT seems is contributive to the characterization of the wide variety of lung abnormalities in PSS. Airway disease alone or in association with the presence of varying degrees of interstitial disease represents the main findings in accordance with earlier reports. Unexpectedly, almost half of the patients had thin-walled cysts on the HRCT scans, which etiology is unclear but could be associated with areas of ground-glass attenuation indicating LIP.
15369016 UK patients with primary Sjögren's syndrome are at increased risk from clinical depressio 2004 Sep OBJECTIVE: This study was undertaken to assess the presence and degree of anxiety and depression in a group of UK patients with primary Sjögren's syndrome (1 degrees SS). DESIGN: Cross-sectional. SETTING: Department of Oral Medicine, Liverpool University Dental Hospital. SUBJECTS: Eighty adult patients; 40 diagnosed with 1 degrees SS according to the revised European Criteria and 40 age/gender-matched controls with no history of chronic illness. INTERVENTION: Hospital Anxiety and Depression Scale (HADS), a self-administered questionnaire designed to evaluate the presence and degree of anxiety and depression in a clinical setting. MAIN OUTCOME MEASURES: Age, gender, Hospital Anxiety and Depression Scale (HADS). RESULTS: Forty patients with 1degrees SS and 40/age/gender-matched controls completed the HADS. Scores for anxiety in both the 1 degrees SS and control groups showed no statistically significant difference. Patients with 1 degrees SS had statistically significant higher, mean HADS scores for depression than the controls. There was an increased prevalence of 'definite' clinical depression in the 1 degrees SS group. CONCLUSION: Patients with 1 degrees SS appear to be at increased risk from clinical depression. Early recognition and appropriate intervention is therefore essential to reduce the negative impact of depression on the patient's quality of life and outcome of their disease.
12910567 Treatment of primary Sjögren's syndrome with low-dose human interferon alfa administered 2003 Aug 15 OBJECTIVE: This study tested the safety and efficacy of human interferon (IFN) alfa for treatment of salivary hypofunction and dry mouth symptoms in primary Sjögren's syndrome patients. METHODS: Combined results are reported from 2 phase III clinical trials in which a total of 497 subjects with primary Sjögren's syndrome received 150 international units of human IFN alfa or matching placebo 3 times per day for 24 weeks by the oromucosal route. RESULTS: Subjects given IFN alfa had a significantly (P = 0.01) greater mean increase in unstimulated whole saliva (UWS) flow, compared with subjects given placebo. In IFN alfa patients, increases in UWS correlated positively and significantly with improvements noted in 7 of 8 symptoms associated with oral and ocular dryness. The coprimary endpoints of stimulated whole saliva flow and oral dryness were not significantly improved in the IFN alfa group relative to placebo. No significant differences were found between the groups with respect to overall adverse event incidence or severity. CONCLUSION: IFN alfa given at low dosage by the oromucosal route can significantly increase UWS flow in patients with primary Sjögren's syndrome, without causing significant adverse events.
12755067 [Two cases of primary biliary cirrhosis accompanied with severe keratoconjunctivitis sicca 2003 Apr BACKGROUND: Primary biliary cirrhosis(PBC) is occasionally associated with Sjögren syndrome and results in liver cirrhosis. It occurs particularly in women, middle-aged or older, and is characterized by the presence of anti-mitochondrial antibody (AMA). We diagnosed PBC in 2 patients with severe keratoconjunctivitis sicca (KCS). CASE 1: A 45-year-old woman was diagnosed with PBC. A test for the presence of AMA was positive and liver dysfunction was detected. Tests for the presence of anti-SSA antibody and anti-SSB antibody were also positive. Signs of severe sicca syndrome observed in the oral cavity and in the eyes were compatible with signs of Sjögren syndrome. Furthermore, superior limbic keratoconjunctivitis was also observed. CASE 2: A 57-year-old woman was diagnosed with PBC and Sjögren syndrome. She also had thyroiditis and severe KCS. Tests for the presence of AMA, anti-SSA antibody, and anti-SSB antibody were positive. In both cases, eye drops were not effective as a treatment for the KCS, but lacrimal punctal occlusion with cauterization was effective. CONCLUSION: PBC should be looked on as a disease that may possibly promote severe KCS.
15523118 Serious infections associated with anticytokine therapies in the rheumatic diseases. 2004 Nov The ability to target and neutralize macrophage-derived inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), has emerged in recent years as one of the most important advances in the treatment of rheumatoid arthritis, Crohn's disease, and several other systemic inflammatory diseases. In rheumatoid arthritis, for example, these biological agents rapidly reduce signs and symptoms of joint inflammation and profoundly slow the progression of joint damage. However, data that have emerged following Food and Drug Administration approval of these agents have alerted clinicians to an increased likelihood of opportunistic infections in patients treated with these agents, particularly tuberculosis. The effect of TNF inhibition on the frequency of infection with more common bacterial pathogens is less clear. Animal models of tuberculosis and other opportunistic infections have demonstrated the importance of TNF-alpha in controlling and containing intracellular pathogens. The spectrum of infections reported to date in the setting of anti-TNF-alpha treatment is reviewed here. In addition, relevant animal data illustrating potential mechanistic roles for TNF-alpha in host responses to infection are also reviewed.
12947264 Inflammatory aortic aneurysm is associated with increased incidence of autoimmune disease. 2003 Sep OBJECTIVE: It has been suggested that certain genetic risk factors indicative of an autoimmune mechanism can be identified in patients with inflammatory aortic aneurysm (IAA). We therefore investigated whether there was a higher incidence of autoimmune diseases in patients with IAA. Further, we explored risk factors, need for in-hospital resources, and early results of treatment, in a case-control study in a university hospital setting. Material and methods From 1983 to 1994, 520 patients were operated because of abdominal aortic aneurysm (AAA). Thirty-one patients had IAA. Control subjects were matched for aneurysm rupture, emergency or elective hospital admission, and date of operation. Two noninflammatory AAA were included for every IAA. RESULTS: Of the 31 patients with IAA, 6 patients (19%) had autoimmune disease, compared with none of the control subjects (P =.0017). Two patients had rheumatoid arthritis, 2 patients had systemic lupus erythematosus, 1 had giant cell arteritis, and 1 patient had an undifferentiated seronegative polyarthritis diagnosed as rheumatoid arthritis. Nineteen patients (61%) with IAA had involvement of the duodenum, and 8 patients (26%) had hydronephrosis with ureteral involvement. Operating time was longer in the IAA group, which also had a higher need for blood transfusion. Hospital stay, intensive care unit stay, and 30-day mortality were similar in the two groups. CONCLUSION: Except for longer operating time and more need for blood transfusions in the IAA group, use of hospital resources was similar after operations to treat IAA or noninflammatory AAA. The study findings indicate an association between IAA and autoimmune disease. This is in accordance with other reports that showed a genetic risk determinant mapped to the human leukocyte antigen (HLA) molecule in these patients. Further research is necessary to explore whether IAA might be a separate entity with a role of antigen binding in the origin of the disease.
15338034 High variability of peptidylarginine deiminase 4 (PADI4) in a healthy white population: ch 2004 Nov Seven single nucleotide polymorphisms (SNPs) of the peptidylarginine deiminase 4 (PADI4) gene have recently been reported to be strongly associated with rheumatoid arthritis in Japanese individuals. These SNPs are located in or close to exons 2-4 of PADI4 and are organized in at least four different haplotypes. However, a detailed sequencing-based characterization of the PADI4 gene in other populations is still lacking. We therefore analyzed exons 2-4 of the PADI4 gene in 102 healthy white Germans individuals by DNA sequencing and characterized new variants and haplotypes by a novel haplotype-specific sequencing-based approach. The haplotypes 2/3 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*T, padi4_95*C, padi4_96*C), and haplotype 4 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*C, padi4_95*G, padi4_96*T) conferring susceptibility to rheumatoid arthritis were detected at frequencies of 30.9% and 7.8%, respectively. In addition, three novel coding SNPs in exons 2, 3, and 4, and three SNPs in introns 2 and 3 located near the exon-intron boundaries were identified in 11 individuals (10.8%). The so-called nonsusceptibility haplotype 1 (padi4_89*A, padi4_90*C, padi4_92*C, padi4_94*C, padi4_104*C, padi4_95*G, padi4_96*T) occurred at a frequency of 58.3%. Additionally, we identified a closely related novel haplotype, haplotype 1B (2.9%), that differs from haplotype 1 only by padi4_92*G/padi4_96*C. This haplotype was not described in the Japanese population. Our results indicate that the PADI4 gene exhibits a remarkable variability and a rather complex haplotypic organization. Further studies on disease association of PADI4 should be performed by haplotype-specific sequencing-based approaches to identify the exact genotype of the PADI4 fragment of interest.
14872510 Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of colla 2004 Feb OBJECTIVE: Interleukin-17 (IL-17) is a proinflammatory cytokine that is expressed in the synovium of rheumatoid arthritis (RA) patients. This T cell cytokine is implicated in the initiation phase of arthritis. However, the role of IL-17 during the effector phase of arthritis has still not been identified; this was the objective of the present study. METHODS: Mice with collagen-induced arthritis (CIA) were treated with polyclonal rabbit anti-murine IL-17 (anti-IL-17) antibody-positive serum or normal rabbit serum after the first signs of arthritis. In addition, during a later stage of CIA mice were selected and treated with anti-IL-17 antibody or control serum. Arthritis was monitored visually, and joint pathology was examined radiologically and histologically. Systemic IL-6 levels were measured by enzyme-linked immunosorbent assay, and local synovial IL-1 and receptor activator of NF-kappaB ligand (RANKL) expression was analyzed using specific immunohistochemistry. RESULTS: Treatment with a neutralizing anti-IL-17 antibody after the onset of CIA significantly reduced the severity of CIA. Radiographic analysis revealed marked suppression of joint damage in the knee and ankle joints. Histologic analysis confirmed the suppression of joint inflammation and showed prevention of cartilage and bone destruction after anti-IL-17 antibody therapy. Systemic IL-6 levels were significantly reduced after anti-IL-17 antibody treatment. Moreover, fewer IL-1beta-positive and RANKL-positive cells were detected in the synovium after treatment with neutralizing IL-17. Interestingly, initiation of anti-IL-17 antibody therapy during a later stage of CIA, using mice with higher clinical arthritis scores, still significantly slowed the progression of the disease. CONCLUSION: IL-17 plays a role in early stages of arthritis, but also later during disease progression. Systemic IL-6 was reduced and fewer synovial IL-1-positive and RANKL-positive cells were detected after neutralizing endogenous IL-17 treatment, suggesting both IL-1-dependent and IL-1-independent mechanisms of action. Our data strongly indicate that IL-17 neutralization could provide an additional therapeutic strategy for RA, particularly in situations in which elevated IL-17 may attenuate the response to anti-tumor necrosis factor/anti-IL-1 therapy.