A survey of European and Canadian rheumatologists regarding the treatment of patients with ankylosing spondylitis and extra-articular manifestations

Ankylosing spondylitis (AS) is a disabling inflammatory disease accompanied by a variety of extra-articular manifestations in a significant number of patients. These manifestations, including Crohn’s disease, ulcerative colitis, psoriasis, and uveitis, share a similar inflammatory mechanism with one another and with AS. Extra-articular manifestations are observed in a larger percentage of patients with AS and spondyloarthritides (SpAs) than the normal population; therefore, it is important to identify these and other inflammatory-mediated conditions and consider them when treating SpAs. How rheumatologists approach patients with both AS and extra-articular manifestations may lead to a better understanding of what treatment approaches could be taken to optimize patient outcomes. Rheumatologists (N = 453) from five European countries and Canada who treat AS were surveyed to determine treatment practices and management of both AS and its associated extra-articular manifestations. Most rheumatologists (93%) believe AS could be diagnosed earlier as the average time between symptom onset and diagnosis was approximately 4 years. In total, 60% routinely screen patients with AS for extra-articular manifestations, although this varied considerably across countries. The majority (97%) agrees that controlling inflammation is critical during treatment, and patients with extra-articular manifestations tend to have poorer prognoses than those patients with only axial AS. Treatment considerations varied depending on whether patients presented with only axial AS or had extra-articular manifestations, where use of biologics became more common. Rheumatologists agree that patients with both AS and extra-articular manifestations require a different treatment strategy than patients with AS alone. Results of this survey highlight areas where rheumatologists differ in their clinical management of patients with AS including tools used for disease assessment and the routine screening, or lack thereof, for other inflammatory diseases. This evidence may suggest aspects within clinical practice where modifications may be made in order to optimize patient outcomes.     

IgA containing immune complexes and hematuria in ankylosing spondylitis. A prospective longitudinal study

The occurrence of circulating immune complexes containing IgA (IgA-IC) was studied in groups of patients with ankylosing spondylitis (AS) selected for the presence or absence of hematuria. In studies done with 4 kinds of assays, IgA-IC were found more frequently and in higher titers in the 18 patients with AS with hematuria than in the 40 patients with AS without hematuria. Comparison of clinical indices of disease activity in these patient groups showed that the disease was more active in patients with AS with hematuria. Our findings confirm those made in a previous retrospective study on the relation between hematuria and circulating IgA-IC in AS and suggest that circulating IgA-IC play a role in the pathogenesis of hematuria in AS.     

Serum IgA to enterobacteria in ankylosing spondylitis

The aetiology of ankylosing spondylitis (AS) may involve certain enterobacteria. It is therefore interesting that serum polymeric IgA, a precursor of secretory IgA, was statistically elevated in active AS (n = 35) and that levels were comparable to those found in yersiniosis (n = 12); this might indicate antigenic stimulation by bacteria which are present in the intestines of AS patients. However, specific serum IgA to the incriminated enterobacteria Klebsiella, Shigella and Yersinia, as determined by ELISA, was not raised in the above AS patients. Nor were these titres raised in patients with idiopathic reactive arthritis (n = 21). In contrast, yersiniosis (n = 12) and shigellosis (n = 96) patients displayed marked increases in specific serum IgA titres to the respective infectants. It is proposed that AS may involve a set of enterobacteria rather than a few suspected species. Thus, despite the lack of raised group averages, screening of individual patients for specific IgA to several indicated bacteria might disclose whether or not raised serum IgA is related to enterobacterial activity. Apart from this, the above supports other reports indicating that serum IgA may be a useful parameter to assist in monitoring of disease activity in AS. Finally, it is suggested that study of a homogeneous group of reactive arthritis patients might facilitate aetiological research of seronegative arthropathies such as AS.     

Immune complexes in ankylosing spondylitis.

Immune complexes have been reported in ankylosing spondylitis (AS) and may implicate infectious agents. Serum samples from 49 patients with AS were assayed for immune complexes by polyethylene glycol precipitation, followed by radial immunodiffusion and pepsinogen binding immunoassay. Both methods showed increases in IgA containing immune complexes, which correlated with serum IgA and with IgA rheumatoid factor concentrations, but did not show increases in other immune complex components. Increased immune complexes were associated with peripheral joint synovitis, but showed no correlation with other clinical or laboratory indices of disease activity. Immune complexes from nine AS serum samples and one AS synovial fluid were electrophoretically separated then probed with anti-Klebsiella pneumoniae, but AS specific antigens were not identified. This study did not suggest a major role for immune complexes in AS without peripheral disease, nor provide serological evidence for the involvement of klebsiella antigens.     

Increased serum IL-17 and IL-23 in the patient with ankylosing spondylitis

Interleukin 17 (IL-17) is a Th17 cytokine associated with inflammation, autoimmunity, and defense against some bacteria; it has been implicated in many chronic autoimmune diseases including psoriasis, multiple sclerosis, and systemic sclerosis. However, whether IL-17 plays a role in the pathogenesis of ankylosing spondylitis (AS) remains unclear. To analyze the content of IL-17 and IL-23 in the serum from patients with AS compared with health control subject, 50 patients with AS and 43 healthy volunteers were recruited. Serum IL-17 levels were examined by enzyme linked immunosorbent assay (ELISA). Statistic analyses were performed by SPSS 13.0. Results show that the serum IL-17 and IL-23 levels were significantly elevated in AS patients as compared with normal controls. Nevertheless, no associations of serum IL-17 and IL-23 levels with clinical and laboratory parameters were found; no significant difference regarding serum IL-17 and IL-23 levels was found between less active AS and more active AS. However, there was a strong positive association between the serum levels of IL-17 and IL-23 in the AS patients. Our results indicate increased serum IL-17 and IL-23 levels in AS patients, suggesting that this two cytokine may play critical roles in the pathogenesis of AS. Therefore, further studies are required to confirm this preliminary data.     

Spondyloarthropathy and rheumatoid arthritis in Alaskan Yupik Eskimos

In a Yupik Eskimo population, the prevalence, incidence and clinical features of rheumatoid arthritis (RA) were similar to those described for the United States population in general. More frequent than RA were seronegative spondyloarthropathic disorders, many of which could not be classified by existing disease criteria. Of the adult patients with spondyloarthropathy only half could be classified as having Reiter's syndrome (RS), ankylosing spondylitis (AS) or psoriatic spondylitis. The remaining patients had many signs and symptoms consistent with spondyloarthropathy, but they either did not meet the diagnostic criteria for any specific disease or had features pathognomonic of more than one. The clinical manifestations of the patients who did not meet standard disease definitions are summarized and compared to those of the patients with RS, AS and psoriatic spondylitis. Because of the many shared features, we believe that these as yet unclassified disease states belong with AS and RS in a single spondyloarthropathic disease spectrum and should be defined and recognized as such.     

Failure to find C1q-binding material and anti-IgG antibodies in ankylosing spondylitis.

C1q-binding immune complexes (C1C), anti-IgG antibodies (anti-IgG Ab), and complement levels were investigated in the serum of 37 patients with ankylosing spondylitis (AS). In all these studies the mean levels observed in patients with AS were similar to those in 31 normal subjects. Moreover, no significative difference in either CIC or anti-IgG Ab levels was observed when the patients were classified in different clinical forms according to the localisation (peripheral and central) or to the gravity (mild and severe) of the AS. In a parallel study increased CIC and anti-IgG Ab levels were found in most of the 81 patients with seropositive or seronegative rheumatoid arthritis.     

Atypical clinical presentation of ankylosing spondylitis

OBJECTIVES: To describe a subgroup of patients with ankylosing spondylitis (AS), whose disease evolved without the characteristic inflammatory back pain or significant disability. METHODS: Three patients who were diagnosed in their late 5th decade of life as having AS are described. Information about asymptomatic cases of AS or patients who were unaware of their disease was gathered from case reports and from studies involving HLA-B27-positive individuals. Another source of information derived from studies that investigated conditions known to be a complication of AS, such as heart block or aortic regurgitation. RESULTS: The data collected from the literature suggest that 1.5% to 10% of the patients with AS are asymptomatic or have very mild disease. These patients are diagnosed late in the course of the disease. CONCLUSIONS: Because of the mild nature of the symptoms, the real prevalence of atypical AS is unknown. The information gathered from the literature allows to delineate 4 subgroups of patients with AS: (1) Classic AS with characteristic clinical and radiographic manifestations; (2) Asymptomatic AS with characteristic radiographic findings; (3) Asymptomatic AS with extra-articular features as the presenting manifestations; (4) Symptomatic AS without radiographic supporting evidence. Patients with asymptomatic or mild symptoms deserve more attention, because a better understanding of the factors that affect the expression of pain in different individuals may generate better pain control therapies.     

Evaluation of paraoxonase and arylesterase activities in Egyptian patients with ankylosing spondylitis

The role of paraoxonase (PON) and arylesterase (ARE) in the pathogenesis of inflammatory arthritis has been investigated, and their serum levels have been evaluated, but clinical study concerning PON1 and ARE and ankylosing spondylitis (AS) is little reported in literature. The aim of this study was to investigate PON1 and ARE activities in AS in comparison with healthy persons and their relation with the disease activity parameters. 35 AS patients and 35 healthy controls (matched for age and sex) participated. Disease activity of AS patients was assessed clinically according to the Bath AS disease activity index, and AS functional impairment was assessed using the Bath AS Functional Index. Serum samples were collected from all subjects to evaluate serum PON1, ARE activities, and lipid profile. The mean serum triglycerides, total cholesterol, and low density lipoprotein (LDL) were significantly higher in the AS patients than in controls, while the high-density lipoprotein (HDL) is significantly lower in the AS patients than controls. Serum PON1 and ARE activities were significantly lower in AS patients than in controls, while malondialdehyde (MDA) was significantly higher. AS patients with active disease had significantly higher serum triglycerides, total cholesterol, LDL and MDA while lower HDL, PON1 and ARE than those with no active AS. Decrease in the PON1/ARE activity leading to generation of oxidative stress may play an important role in the pathogenesis of AS. Moreover, it seems that activity of PON1/ARE in patients with AS is strictly correlated with the activity of the inflammatory process.     

Does anti-tnf therapy cause any change in platelet activation in ankylosing spondylitis patients?

Recently, it has been reported that ankylosing spondylitis (AS) was characterised by endothelial dysfunction and the development of atherosclerotic complications. In this study, we evaluated platelet and endothelial activation parameters in AS patients. Fiftynine AS patients and 22 healthy controls were included. The clinical features and acute phase parameters were evaluated. In all patients and healthy controls, platelet-monocyte complexes (PMC), platelet-neutrophil complexes, basal and ADP-stimulated P-selectin (CD62P) expression were determined by flow cytometry; soluble E-selectin (sE-selectin) and soluble CD40L (sCD40L) were determined by ELISA. AS patients were divided into two groups as active and inactive by using BASDAI. In 15 AS patients, the evaluated parameters were assessed before and after 12 weeks of anti-TNF therapy. PMC and sCD40L levels in AS patients were significantly higher than in the control group (P values 0.013 and 0.016). The evaluated variables were similar in active and inactive AS groups (P > 0.05). There were no significant changes in platelet and endothelial activation parameters in AS patients after anti-TNF therapy (P > 0.05). Platelet activation which is reflected by high levels of PMC and sCD40L might be responsible for the increased frequency of atherosclerosis in AS. The platelet activation in our AS patients was not associated with disease activity and did not improve after anti-TNF therapy.     

Serum levels of secretory IgA in ankylosing spondylitis

An ELISA test was performed in order to measure the serum levels of secretory IgA (sIgA) in 51 patients with ankylosing spondylitis (AS) and 30 healthy controls. Raised values of sIgA were found in AS patients compared to controls. Patients with active disease, defined by clinical criteria, showed a significant elevation of serum sIgA compared to healthy controls (p = 0.03) or to patients with inactive disease (p = 0.02). A positive correlation between total serum IgA and sIgA was found (p = 0.001). Our findings further support the role of the mucosal stimulation in the pathogenesis of AS.     

Ankylosing spondylitis-related secondary amyloidosis responded well to etanercept: a report of three patients

Secondary (AA) amyloidosis is one of the most significant complications of ankylosing spondylitis (AS) that frequently leads to proteinuria and renal dysfunction. Anti-tumor necrosis factor alpha (anti-TNF) agents are promising in inducing clinical remission by suppressing systemic inflammation in AA amyloidosis. We report three cases with AS-related AA amyloidosis that responded well to etanercept therapy. Despite treatment with disease modifying anti-rheumatic drugs, all three patients had active AS, marked proteinuria, impaired renal function, and low serum albumin level. During 1-year treatment with etanercept, all patients experienced gradual improvement in all of these parameters.     

Antinuclear antibodies in ankylosing spondylitis, psoriatic arthritis, and psoriasis.

Granulocyte-specific antinuclear antibodies (GS-ANA) were detected in the sera of 5 of 88 patients with ankylosing spondylitis (AS) and in 7 of 52 cases of psoriatic arthritis (PsA), but were not found in 91 patients with malignant or non-malignant chest disease nor in 25 cases of psoriasis. Organ non-specific ANA were present in serum from 6 cases of AS and 1 of PsA. None of the sera gave significant levels for soluble immune complexes as detected by a C1q-binding assay. The presence of antinuclear antibodies was not associated with clinical features or drug therapy in either AS or PsA.     

Investigation of the role of ANKH in ankylosing spondylitis

OBJECTIVE: The ank/ank mouse develops a phenotype similar to ankylosing spondylitis (AS) in humans. ANKH, the human homolog of the mutated gene in the ank/ank mouse, has been implicated in familial autosomal-dominant chondrocalcinosis and autosomal-dominant craniometaphyseal dysplasia. This study was undertaken to investigate the role of ANKH in susceptibility to and clinical manifestations of AS. METHODS: Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls. Linkage to the ANKH locus was assessed in 185 affected-sibling-pair families. RESULTS: Five single-nucleotide polymorphisms were identified within the coding region and flanking splice sites. No association between either susceptibility to AS or its clinical manifestations and these novel polymorphisms, or between disease susceptibility and 3 known promoter variants, was seen. No linkage between the ANKH locus and AS was observed. Multipoint exclusion mapping rejected the hypothesis of a locus of a magnitude lambda>/=1.4 (logarithm of odds score <-2) (equivalent to a genetic contribution of >10% to the AS sibling recurrence risk ratio) within this area contributing to AS. CONCLUSION: These findings indicate that ANKH is not significantly involved in susceptibility to or clinical manifestations of AS.     

Serum amyloid P component-DNA complexes are decreased in systemic lupus erythematosus. inverse association with anti-dsDNA antibodies

OBJECTIVE: To study serum levels of serum amyloid P component (SAP) and SAP-DNA complexes in a population-based cohort of patients with systemic lupus erythematosus (SLE). METHODS: The study population comprised 82 unselected patients of predominantly Scandinavian ancestry with SLE according to current classification criteria. Serum samples were collected at baseline and serially for up to 2 years. SAP component and SAP-DNA complexes were measured by ELISA. Associations between SAP-DNA and clinical manifestations or serological findings were analyzed. Ninety healthy, age-matched blood donors served as controls. RESULTS: SLE patients had normal serum concentrations of SAP, whereas SAP-DNA complexes were decreased. Two-thirds of the SLE patients tested persistently SAP-DNA complex-negative. There was no relationship between the occurrence of SAP-DNA complexes and clinical manifestations. SAP-DNA-negative patients tended to have lower leukocyte counts and complement C3 levels, and higher erythrocyte sedimentation rates and C3d levels versus SAP-DNA-positive patients. There was an inverse association between the occurrence of anti-double-stranded DNA (anti-dsDNA) antibodies and SAP-DNA complexes. Co-occurrence of SAP-DNA complexes and anti-dsDNA antibodies was demonstrated in only one SLE patient, implying that 81/82 patients were discordant for the presence of anti-dsDNA antibodies and SAP-DNA complexes. CONCLUSION: The decreased level of SAP-DNA complexes in SLE patients and the inverse relationship between these complexes and anti-dsDNA antibody supports the concept that SAP component is implicated in the clearance of cell nuclear debris.     

IgE and IgE-rheumatoid factors in circulating immune complexes in rheumatoid arthritis.

The sera of 21 patients with rheumatoid arthritis (RA), 11 patients with systemic lupus erythematosus (SLE), and 20 healthy subjects were analysed for the presence of IgE in immune complex fractions. These fractions were isolated by polyethylene glycol precipitation and gel filtration. Thirteen sera from RA patients contained IgE immune complexes (IC) and 11 of these were from patients with extra-articular manifestations. One SLE and none of the control sera contained such material. The serum IgE level did not correlate with IgE content of the IC fractions. Higher mean serum IgE levels were found in RA patients with extra-articular complications than in controls or RA patients with joint disease only, but the differences did not reach statistical significance. IgE anti-rabbit IgG (IgE rheumatoid factors) could be demonstrated in some IgE positive IC fractions. Antibodies to IgE, in 2 instances characterised as belonging to IgG class, were also found in ICs. This suggests the presence of anti IgE complexes. It is suggested that IgE, including some with rheumatoid factor activity, is contained in complexes which may be involved in some extra-articular manifestations of RA.     

肺炎支原体感染与强直性脊柱炎活动性的研究

目的 研究成人强直性脊柱炎(AS)患者肺炎支原体(MP)感染与疾病活动性的关系.方法 选取我院门诊AS患者66例;对照组选取类风湿关节炎(RA)31例,骨关节炎(OA)25例,健康人群(NC)36名.根据抗肺炎支原体抗体(anti-MP IgM)将AS患者分成MP感染组和非MP感染组,比较和分析4周以内上呼吸道感染史、白细胞、疾病活动指数(BASDAI)、红细胞沉降率(ESR)、C反应蛋白(CRP)、免疫球蛋白以及骶髂关节损害程度、脊柱活动度(Schober测量和胸廓活动度).结果 66例AS患者抗MP抗体检测发现,阳性检出率为52%(34/66),与RA(6%)、OA(4%)、NC(11%)比较,差异有统计学意义(P＜0.01).MP感染组的疾病活动也显著高于非MP感染组,其中BASDAI(4.0±1.1对3.0±1.9,P=0.017),ESR[(44±32)mm/1 h对(28±23)mm/1 h,P=0.029],CRP[(40±38)mg/L对(22±21)mg/L,P=0.025],血清总IgG水平[(18±3)g/L对(16±5)g/L,P=0.027],但与总IgA和IgM无关.两组的骶髂关节分级、Schober测量和胸廓扩张度差异无统计学意义.抗MP抗体阳性的AS患者中只有44%出现呼吸道症状,但有呼吸道症状的AS患者中,71%的患者抗MP抗体阳性,与无呼吸道症状组比较,差异具有统计学意义(P=0.027).结论 AS患者的MP感染与疾病的活动性密切相关,可能是AS发病的主要诱发因素.     

Serum prolidase level in ankylosing spondylitis: low serum levels as a new potential gold standard biomarker for disease activity

Ankylosing spondylitis (AS) is a chronic inflammatory disorder that mainly affects the sacroiliac joints and axial skeleton. The aim of this study was to assess serum prolidase level (SPL) and its association with disease activity in patients with AS. This prospective study included 75 AS patients. Thirty age- and gender-matched healthy controls were enrolled. AS patients were considered as active if BASDAI score was ≥4 or inactive if BASDAI score was <4. There were 34 AS patients in the active group and 41 AS patients in the inactive group. Anti-TNF-monoclonal antibody treatment was started in patients in the active group. These active patients were reassessed 6 months later. BASDAI, ASDAS, visual analogue scale, short-form-general health survey questionnaire, C-reactive protein, erythrocyte sedimentation rate and SPL were measured in all AS patients before and after treatment. The SPL was significantly lower in inactive AS patients than in control group, and also, SPL was significantly lower in active AS patients than in inactive patients. All activity parameters were successful in separating active and inactive AS patients. However, the only parameter that could distinguish active patients from inactive patients was prolidase. The optimum cutoff point of SPL to identify patients with active AS was 23.13 ng/mL with sensitivity, specificity, positive predictive value and negative predictive value of 100 %. Serum prolidase level was successful in measuring disease activity and had as high sensitivity and specificity as BASDAI and was superior to other activity parameters.     

Soluble interleukin 2 receptor levels in serum and its relationship to T cell abnormality and clinical manifestations of the disease in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is associated with alterations in immune regulation that results in T cell activation and release of the soluble interleukin 2 receptors (sIL-2R) in serum. SLE, a disease with varied clinical manifestations also has regulatory T cell subset abnormalities in blood. Levels of sIL-2R in serum of patients with active SLE were higher than in those with other common rheumatic diseases. Patients with active SLE and an increased percentage of CD4+ CDw29+ helper inducer (memory) and decreased percentage of CD4+ CD45R+ suppressor inducer (virgin) T cell subsets in blood demonstrated elevated levels of sIL-2R in serum. When compared with clinical manifestations of the disease, the sIL-2R levels in the sera of the patients with active SLE and thrombocytopenia were higher (mean 1710 units/ml) than those in active SLE with nephrotic syndrome (mean 1230 units/ml) or in active SLE with central nervous system disease (mean 1157 units/ml). However, patients with active SLE with humoral immunodeficiency (hypogammaglobulinemia) had highly elevated levels of sIL-2R in serum as compared to other patients with active SLE. The highly elevated levels of sIL-2R in serum may indicate that in vivo T cell activation plays an important role in this disease.