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1.
Arthritis rheumatol ; 68(2)Feb. 2016.
Article in English | BIGG - GRADE guidelines | ID: biblio-964633

ABSTRACT

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.(AU)


Subject(s)
Humans , Spondylitis, Ankylosing/drug therapy , Spondylitis, Ankylosing/therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antirheumatic Agents/therapeutic use , Spondylarthritis/drug therapy , Glucocorticoids/therapeutic use , Physical Therapy Modalities , Tumor Necrosis Factor-alpha/therapeutic use , Adalimumab/therapeutic use , Infliximab/therapeutic use , Etanercept/therapeutic use
2.
Ann Rheum Dis ; 74(7): 1387-93, 2015 Jul.
Article in English | MEDLINE | ID: mdl-24651623

ABSTRACT

OBJECTIVE: To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). METHOD: We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon-intron boundaries, and 5 kb flanking DNA in the 5' and 3' UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into 'mild' and 'severe' groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. RESULTS: Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10(-5)), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10(-3)). There was no observed association between radiographic severity and HLA-B*27. CONCLUSIONS: These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.


Subject(s)
Bone Resorption/genetics , Cervical Vertebrae/diagnostic imaging , Genetic Association Studies , Lumbar Vertebrae/diagnostic imaging , Osteogenesis/genetics , Spondylitis, Ankylosing/diagnostic imaging , Spondylitis, Ankylosing/genetics , Adult , Cyclooxygenase 1/genetics , Exons/genetics , Female , Genotype , Haplotypes/genetics , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Radiography , Receptor Activator of Nuclear Factor-kappa B/genetics , Severity of Illness Index
3.
Clin Exp Rheumatol ; 32(3): 424-31, 2014.
Article in English | MEDLINE | ID: mdl-24387974

ABSTRACT

OBJECTIVES: A significant proportion of patients with juvenile spondyloarthritis (JSpA) are refractory to treatment with established medications. The objective of this study was to assess long-term efficacy of treatment with anti-TNF agents in patients with JSpA. METHODS: An observational study of 16 patients with JSpA from 3 centres treated with infliximab (n=10) and etanercept (n=6) was performed, with a median follow-up period of 7.2 years. Prospective data was collected according to a standardized protocol. Outcomes examined were TEC, TAJC, markers of inflammation (ESR, CRP), functional assessments (C-HAQ, BASDAI, BASFI), and ongoing requirement for anti-TNF treatment. RESULTS: 13/16 patients (83%) had achieved clinical remission 6 months into the treatment. Improvement was sustained over time, with a median TAJC and TEC of 0 at any time point after 6 weeks. 6/16 patients (38%) showed a flare of arthritis after a median of 3.5 years. Two patients with hip disease prior to treatment required an arthroplasty 3 and 8 years post anti-TNF initiation. Patients showed progression of sacroiliitis with median modified New York score of 1 (range 0-3) at time of diagnosis and 3 (range 0-4) at last follow-up (p=0.002). Median BASDAI at last follow up was 1.6, median BASFI 3.1. Two patients developed transient reactions (one generalised, one local); no patient developed other adverse effects during the study. CONCLUSIONS: Anti-TNF treatment in JSpA refractory to standard treatment results in good long-term disease control except for pre-existing hip disease. However, radiographic evidence suggests inferior efficacy for control of sacroiliac joint disease.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Immunoglobulin G/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Spondylarthritis/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adolescent , Arthritis, Juvenile/drug therapy , Child , Etanercept , Female , Follow-Up Studies , Humans , Infliximab , Longitudinal Studies , Male , Sacroiliitis/drug therapy , Treatment Outcome
4.
Ann Rheum Dis ; 70(6): 896-904, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21540199

ABSTRACT

This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made - if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.


Subject(s)
Practice Guidelines as Topic , Spondylitis, Ankylosing/therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antirheumatic Agents/therapeutic use , Humans , International Cooperation , Spondylitis, Ankylosing/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors
5.
Arthritis Care Res (Hoboken) ; 62(4): 447-54, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20391497

ABSTRACT

OBJECTIVE: The prevalence of sacroiliac (SI) joint abnormalities in a primary low back pain population remains unresolved. The aims of our study were to define the prevalence of SI joint disease in this cohort, and to identify clinical features that might accurately predict radiographic changes in the SI joint and spine. METHODS: Lumbar spine and anteroposterior pelvis radiographs taken over a 3-year period for the evaluation of back pain at a major chiropractic college were scored for the presence of inflammatory or degenerative features. Data were subsequently extracted by means of a predetermined template from the clinical notes. The outcomes were correlated using Spearman's correlation coefficients. RESULTS: We identified 315 patients (173 men, 142 women), ages 18-60 years. Of these, 100 patients (31.7%) demonstrated SI joint abnormalities: 75 (23.8%) degenerative, 25 (7.9%) inflammatory. Sex was strongly associated with type of SI joint pathology; degenerative disease was predominantly found in women (68%), whereas inflammatory disease was predominantly found in men (63%). In women there was no correlation between degenerative SI joint abnormalities and degenerative changes in the lumbar spine. Of the clinical descriptors evaluated, none were associated with the radiographic findings with the exception of buttock pain, which was associated with inflammatory sacroiliitis. Neither being overweight nor pregnancy history was associated with degenerative changes in the SI joint. CONCLUSION: In a primary back pain cohort, degenerative SI joint disease may be an under-recognized clinical entity. It is strongly influenced by sex but is unrelated to degenerative changes in the lumbar spine. Currently proposed clinical discriminators performed poorly in correlating with radiographic changes in the SI joint.


Subject(s)
Arthritis/epidemiology , Back Pain/diagnostic imaging , Intervertebral Disc Degeneration/epidemiology , Sacroiliac Joint/diagnostic imaging , Adolescent , Adult , Arthritis/diagnostic imaging , Arthritis/immunology , Back Pain/epidemiology , Back Pain/immunology , Cohort Studies , Female , Humans , Intervertebral Disc Degeneration/diagnostic imaging , Lumbar Vertebrae/diagnostic imaging , Male , Middle Aged , Ontario/epidemiology , Osteosclerosis/diagnostic imaging , Osteosclerosis/epidemiology , Prevalence , Radiography , Sacroiliac Joint/immunology , Sex Distribution , Spinal Osteophytosis/diagnostic imaging , Spinal Osteophytosis/epidemiology , Young Adult
6.
Arthritis Rheum ; 62(5): 1298-307, 2010 May.
Article in English | MEDLINE | ID: mdl-20155838

ABSTRACT

OBJECTIVE: Chlamydia trachomatis and Chlamydophila (Chlamydia) pneumoniae are known triggers of reactive arthritis (ReA) and exist in a persistent metabolically active infection state in the synovium, suggesting that they may be susceptible to antimicrobial agents. The goal of this study was to investigate whether a 6-month course of combination antibiotics is an effective treatment for patients with chronic Chlamydia-induced ReA. METHODS: This study was a 9-month, prospective, double-blind, triple-placebo trial assessing a 6-month course of combination antibiotics as a treatment for Chlamydia-induced ReA. Eligible patients had to be positive for C trachomatis or C pneumoniae by polymerase chain reaction (PCR). Groups received 1) doxycycline and rifampin plus placebo instead of azithromycin; 2) azithromycin and rifampin plus placebo instead of doxycycline; or 3) placebos instead of azithromycin, doxycycline, and rifampin. The primary end point was the number of patients who improved by 20% or more in at least 4 of 6 variables without worsening in any 1 variable in both combination antibiotic groups combined and in the placebo group at month 6 compared with baseline. RESULTS: The primary end point was achieved in 17 of 27 patients (63%) receiving combination antibiotics and in 3 of 15 patients (20%) receiving placebo. Secondary efficacy end points showed similar results. Six of 27 patients (22%) randomized to combination antibiotics believed that their disease went into complete remission during the trial, whereas no patient in the placebo arm achieved remission. Significantly more patients in the active treatment group became negative for C trachomatis or C pneumoniae by PCR at month 6. Adverse events were mild, with no significant differences between the groups. CONCLUSION: These data suggest that a 6-month course of combination antibiotics is an effective treatment for chronic Chlamydia-induced ReA.


Subject(s)
Arthritis, Reactive/drug therapy , Azithromycin/administration & dosage , Chlamydia Infections/complications , Chlamydia trachomatis/isolation & purification , Doxycycline/administration & dosage , Rifampin/administration & dosage , Adult , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Antibiotics, Antitubercular/administration & dosage , Antibiotics, Antitubercular/adverse effects , Arthritis, Reactive/microbiology , Arthritis, Reactive/pathology , Azithromycin/adverse effects , Chlamydia trachomatis/genetics , Chlamydophila pneumoniae/genetics , Chlamydophila pneumoniae/isolation & purification , Chronic Disease , DNA, Bacterial/genetics , Double-Blind Method , Doxycycline/adverse effects , Drug Therapy, Combination , Female , Humans , Joints/pathology , Male , Middle Aged , Placebos , Prohibitins , Prospective Studies , Rifampin/adverse effects , Treatment Outcome
7.
Ann Rheum Dis ; 69(1): 297-300, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19103635

ABSTRACT

OBJECTIVES: Studying post-infliximab gene expression changes could provide insights into the pathogenesis of ankylosing spondylitis (AS). METHODS: Gene expression changes were screened by microarray on peripheral blood RNA of 16 AS patients at baseline and 2 weeks post-infliximab, and selected results were confirmed by quantitative real-time (qRT)-PCR. Corresponding serum-soluble LIGHT (sLIGHT) was estimated by ELISA and the fold change in sLIGHT was correlated to the fold change in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and the Bath AS disease activity index. RESULTS: Post-infliximab, 69% of the patients (11/16) achieved an ASAS20 response. Six candidate genes were differentially expressed by microarray; four of which were validated by qRT-PCR. sLIGHT showed the most significant difference. There was good correlation of baseline sLIGHT with CRP (R = 0.60; p = 0.01) and ESR (R = 0.51; p = 0.04). The fold change in sLIGHT correlated with change in both CRP (R = 0.71, p = 0.002) and ESR (R = 0.77, p<0.001). CONCLUSION: LIGHT is significantly downregulated by infliximab. sLIGHT correlated well with changes in inflammatory markers.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Blood Proteins/metabolism , Spondylitis, Ankylosing/drug therapy , Adult , Biomarkers/blood , Blood Sedimentation , C-Reactive Protein/metabolism , Female , Gene Expression Profiling/methods , Humans , Infliximab , Male , Middle Aged , Oligonucleotide Array Sequence Analysis/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , Severity of Illness Index , Spondylitis, Ankylosing/blood , Tumor Necrosis Factor Ligand Superfamily Member 14/blood , Young Adult
8.
Clin Exp Rheumatol ; 27(4 Suppl 55): S26-32, 2009.
Article in English | MEDLINE | ID: mdl-19822042

ABSTRACT

Ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are immune-mediated inflammatory joint diseases with the potential for significant target organ damage. Genetic factors play an important role in defining disease susceptibility. Both diseases are mediated in part by TNF, since anti-TNF therapies have proved effective in both AS and RA. Despite their similarities, the genetic elements associated with the respective diseases differ, most notably in HLA associations, with AS being associated with class I HLA alleles and RA associated with class II HLA alleles. AS has a predilection for axial joints whereas RA targets peripheral joints, but the immunological basis of that distinction is unknown. Autoantibody formation is the immunological hallmark of RA, whereas AS is notable for being a "seronegative" disease. Growing knowledge of new aspects of the host immune response (such as innate immune responses and Th17 cells) is adding to new insights into shared mechanisms of pathogenesis between these two diseases.


Subject(s)
Arthritis, Rheumatoid/immunology , Immunity, Innate/immunology , Spondylitis, Ankylosing/immunology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/genetics , Autoantibodies/blood , Genes, MHC Class I , Genes, MHC Class II , Humans , Spondylitis, Ankylosing/blood , Spondylitis, Ankylosing/genetics
10.
Arthritis Rheum ; 60(5): 1317-23, 2009 May.
Article in English | MEDLINE | ID: mdl-19404951

ABSTRACT

OBJECTIVE: Alterations in antigen processing have been proposed to play a significant role in the pathogenesis of ankylosing spondylitis (AS). A non-major histocompatibility complex gene encoding an endoplasmic reticulum aminopeptidase, ERAP1, has been implicated recently. This study assessed 13 coding single-nucleotide polymorphisms (SNPs) from 5 genes involved in antigen processing (ERAP1, TAP1, TAP2, LMP2, and LMP7) in 3 Canadian cohorts of patients with AS, to address the possibility of gene interactions in disease susceptibility. METHODS: The study involved 992 AS cases and 1,437 controls from 3 centers (472 cases and 451 controls from Alberta, 138 cases and 392 controls from Newfoundland, and 382 cases and 594 controls from Toronto). Most of the patients with AS and healthy, unrelated controls were Caucasians of northern European descent. Single-marker and haplotype associations were determined using an allelic likelihood ratio test in UNPHASED, version 3.0.12, and the WHAP program, respectively. P values for significance of haplotype associations were calculated using a permutation test. RESULTS: A specific ERAP1 haplotype, rs27044/10050860/30187-CCT, was strongly associated with increased risk of AS in all 3 case-control cohorts (pooled odds ratio [OR] 1.81, 95% confidence interval [95% CI] 1.46-2.24; P=7x10(-8)), while a second specific ERAP1 haplotype, rs30187/26618/26653-CTG, reduced the disease risk (pooled OR 0.77, 95% CI 0.67-0.88; P=9x10(-5)). Significant associations were also noted for 3 ERAP1 SNP variants (rs10050860, rs30187, and rs26653), although no significant haplotype interaction between ERAP1 and TAP/LMP loci was evident. CONCLUSION: These data indicate that an AS disease locus may reside on a specific ERAP1 haplotype, and its effect is not multiplicative with contributions from TAP and LMP genes.


Subject(s)
Aminopeptidases/genetics , Genetic Predisposition to Disease/genetics , Spondylitis, Ankylosing/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 2 , ATP Binding Cassette Transporter, Subfamily B, Member 3 , ATP-Binding Cassette Transporters/genetics , Canada , Haplotypes , Humans , Minor Histocompatibility Antigens , Multienzyme Complexes/genetics , Polymorphism, Single Nucleotide , Proteasome Endopeptidase Complex , White People
11.
Ann Rheum Dis ; 68(9): 1407-12, 2009 Sep.
Article in English | MEDLINE | ID: mdl-18782793

ABSTRACT

OBJECTIVES: An important unresolved issue in the pathogenesis and clinical course of ankylosing spondylitis (AS) is whether juvenile-onset AS (JoAS) is a clinical entity in its own right or just an earlier onset variant of adult-onset AS (AoAS). A study was undertaken to address this issue. METHODS: All patients with AS were extracted from the database of a large spondylitis clinic. Those with symptom onset at < or =16 years were compared with those with symptom onset at > or =17 years. Odds ratios (OR) were calculated and adjusted for disease duration and current age. RESULTS: 267 patients with AS were identified; 84 met the criteria for JoAS and 183 met the criteria for AoAS. There were no differences in gender ratio (male: JoAS 81%, AoAS 79%) or in HLA-B27 status (positive: JoAS 75%, AoAS 81%). The axial/peripheral pattern of disease at presentation differed; an exclusively peripheral pattern was seen in 26% with JoAS but in only 4.6% of those with AoAS (p<0.001). There were no differences in disease activity between the two groups. When adjusted for disease duration, axial features were more prominent in AoAS than JoAS as represented by neck pain (OR 2.93 (95% CI 1.54 to 5.55)), neck stiffness (OR 3.39 (95% CI 1.80 to 6.39)), back pain (OR 2.96 (95% CI 1.43 to 6.11)) or back stiffness (OR 3.30 (95% CI 1.50 to 7.28)). AoAS was associated with worse functional and quality of life measures and higher fatigue scores when adjusted for disease duration. CONCLUSIONS: JoAS follows a distinctive clinical course from AoAS. These clinical features are dictated by factors other than male gender and HLA-B27 and warrant further investigation.


Subject(s)
Spondylitis, Ankylosing/diagnosis , Adolescent , Adult , Age Factors , Age of Onset , Child , Female , HLA-B27 Antigen/analysis , Humans , Male , Prognosis , Quality of Life , Radiography , Severity of Illness Index , Spondylitis, Ankylosing/diagnostic imaging , Spondylitis, Ankylosing/pathology , Young Adult
12.
Clin Exp Rheumatol ; 26(1 Suppl 48): S12-7, 2008.
Article in English | MEDLINE | ID: mdl-18570749

ABSTRACT

Autoimmune rheumatic diseases are generally considered as a multifactorial aetiology, mainly genetic susceptibility combined with environmental triggers of which bacteria are considered one of the most prominent. Among the rheumatic diseases where bacterial agents are more clearly involved as triggers are: reactive arthritis (ReA), rheumatic fever (RF) and Lyme disease. The role of bacterial infections in inducing other seronegative spondyloarthritis and antiphospholipid antibody syndrome has been hypothesized but is still not proven. The classic form of ReA is associated with the presence of HLA-B27 and is triggered by the urethritis or enteritis causing pathogens Chlamydia trachomatis and the enterobacteria Salmonella, Shigella, and Yersinia, respectively. But several other pathogens such as Brucella, Leptospira, Mycobacteria, Neisseria, Staphylococcus and Streptococcus have also been reported to cause ReA. RF is due to an autoimmune reaction triggered by an untreated throat infection by Streptococcus pyogenes in susceptible individuals. Carditis is the most serious manifestation of RF and HLA-DR7 is predominantly observed in the development of valvular lesions. Lyme disease is a tick-transmitted disease caused by the spirochete Borrelia burgdorferi. Knowledge is limited about how this spirochete interacts with human tissues and cells. Some data report that Borrelia burgdorferi can manipulate resident cells towards a pro- but also anti-inflammatory reaction and persist over a long period of time inside the human body or even inside human cells.


Subject(s)
Autoimmune Diseases/microbiology , Bacterial Infections/complications , Bacterial Infections/immunology , Rheumatic Diseases/immunology , Rheumatic Diseases/microbiology , Autoimmune Diseases/immunology , Humans , Prohibitins
13.
Rheumatology (Oxford) ; 47(8): 1213-8, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18539622

ABSTRACT

OBJECTIVES: Many AS patients report periods of perceived higher disease activity (flares). This pilot study aims to document disease activity patterns reported by AS patients and examine associations with disease-specific health status measures. METHODS: Consecutive AS patients (n = 114) were asked whether they experience flares, and if they experience symptoms of AS between flares. They were shown the Flare Illustration of disease patterns over time and asked to select the pattern that best described their disease (i) since symptom onset and (ii) in the past year. Associations between reported disease pattern and disease activity (Bath AS Disease Activity Index, BASDAI); functional impairment (Bath AS Functional Index, BASFI); AS Quality of Life (ASQoL); Back Pain (Nocturnal and Overall) and demographic features were assessed in a subsample (n = 83) (statistical significance defined at P 70% of patients) and patterns with constant symptoms since onset (vs intermittent symptoms) were associated with worse health status (ASQoL: P = 0.007; BASDAI: P = 0.029; BASFI: P = 0.013, overall back pain: P = 0.025). CONCLUSIONS: Almost all AS patients report flares in disease activity: 70-80% report constant symptoms with single/repeated flares, while 20-30% report flares with no intermittent symptoms. The former is associated with a significantly poorer health status. These findings will be validated in a prospective study.


Subject(s)
Severity of Illness Index , Spondylitis, Ankylosing/diagnosis , Adult , Aged , Back Pain/etiology , Female , Humans , Male , Middle Aged , Periodicity , Pilot Projects , Psychometrics , Quality of Life , Spondylitis, Ankylosing/complications
14.
Ann Rheum Dis ; 67(3): 346-52, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17967833

ABSTRACT

OBJECTIVE: Evaluate long-term safety and efficacy of etanercept treatment in patients with ankylosing spondylitis (AS). METHODS: Patients with AS who previously participated in a randomised controlled trial (RCT) of etanercept were eligible to enroll in a 168-week open-label extension (OLE). Safety end points included rates of adverse events (AE), serious adverse events (SAE), infections, serious infections and death. Efficacy end points included Assessment in Ankylosing Spondylitis (ASAS20) response, ASAS 5/6 response and partial remission rates. RESULTS: A total of 257 of 277 patients (92%) enrolled in the OLE. After up to 192 weeks of treatment with etanercept, the most common AEs were injection site reactions, headaches and diarrhoea. The exposure-adjusted rate of SAEs was 0.08 per patient-year. The rate of infections was 1.1 per patient-year, and the rate for serious infections was 0.02 per patient-year. No deaths were reported. Of patients who received etanercept in both the RCT and OLE and were still in the trial, 71% were ASAS20 responders at week 96, and 81% were responders at week 192. ASAS 5/6 response rates were 61% at week 96 and 60% at week 144, and partial remission response rates were 41% at week 96 and 44% at week 192. Placebo patients who switched to etanercept in the OLE showed similar patterns of efficacy maintenance. CONCLUSIONS: Etanercept was well tolerated for up to 192 weeks in patients with AS, with no unexpected AEs or SAEs observed. No deaths were reported. Improvements in the signs and symptoms of AS were maintained for up to 192 weeks.


Subject(s)
Antirheumatic Agents/therapeutic use , Immunoglobulin G/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Spondylitis, Ankylosing/drug therapy , Adult , Antirheumatic Agents/adverse effects , Double-Blind Method , Etanercept , Female , Follow-Up Studies , Humans , Immunoglobulin G/adverse effects , Male , Middle Aged , Severity of Illness Index , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors
16.
Ann Rheum Dis ; 65(4): 442-52, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16126791

ABSTRACT

OBJECTIVE: To develop evidence based recommendations for the management of ankylosing spondylitis (AS) as a combined effort of the 'ASsessment in AS' international working group and the European League Against Rheumatism. METHODS: Each of the 22 participants was asked to contribute up to 15 propositions describing key clinical aspects of AS management. A Delphi process was used to select 10 final propositions. A systematic literature search was then performed to obtain scientific evidence for each proposition. Outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, relative risk, number needed to treat, and incremental cost effectiveness ratio were calculated. On the basis of the search results, 10 major recommendations for the management of AS were constructed. The strength of recommendation was assessed based on the strength of the literature evidence, risk-benefit trade-off, and clinical expertise. RESULTS: The final recommendations considered the use of non-steroidal anti-inflammatory drugs (NSAIDs) (conventional NSAIDs, coxibs, and co-prescription of gastroprotective agents), disease modifying antirheumatic drugs, treatments with biological agents, simple analgesics, local and systemic steroids, non-pharmacological treatment (including education, exercise, and physiotherapy), and surgical interventions. Three general recommendations were also included. Research evidence (categories I-IV) supported 11 interventions in the treatment of AS. Strength of recommendation varied, depending on the category of evidence and expert opinion. CONCLUSION: Ten key recommendations for the treatment of AS were developed and assessed using a combination of research based evidence and expert consensus. Regular updating will be carried out to keep abreast of new developments in the management of AS.


Subject(s)
Spondylitis, Ankylosing/therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antirheumatic Agents/therapeutic use , Arthroplasty, Replacement, Hip , Cost-Benefit Analysis , Evidence-Based Medicine , Exercise , Humans , International Cooperation , Physical Therapy Modalities , Spondylitis, Ankylosing/drug therapy , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors
17.
Ann Rheum Dis ; 64(11): 1557-62, 2005 Nov.
Article in English | MEDLINE | ID: mdl-15843448

ABSTRACT

OBJECTIVE: To evaluate the continued safety and durability of clinical response in patients with ankylosing spondylitis receiving etanercept. METHODS: 277 patients who had participated in a previous randomised, double blind, placebo controlled 24 week trial were eligible to continue in this open label extension study. All patients who enrolled in the open label extension (n = 257) received subcutaneous etanercept 25 mg twice weekly for up to 72 weeks, for a combined 96 weeks of cumulative trial and open label experience. For the patients who had received etanercept for 24 weeks in the double blind trial, this represented almost 2 years of continuous etanercept treatment. RESULTS: Patients continuing etanercept treatment had a sustained response for almost 2 years, with 74% achieving an ASsessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks of etanercept treatment. Patients who had received placebo in the preceding double blind trial had similar responses, with 70% of patients attaining an ASAS 20 response after 24 weeks of etanercept treatment and 78% achieving an ASAS 20 response after 72 weeks. Improved spinal mobility was seen in both groups. Etanercept was well tolerated in patients treated for up to 96 weeks. CONCLUSION: The subcutaneous administration of twice weekly doses of etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis for nearly 2 years.


Subject(s)
Antirheumatic Agents/therapeutic use , Immunoglobulin G/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Spondylitis, Ankylosing/drug therapy , Adolescent , Adult , Aged , Antirheumatic Agents/adverse effects , Double-Blind Method , Drug Administration Schedule , Etanercept , Female , Follow-Up Studies , Humans , Immunoglobulin G/adverse effects , Injections, Subcutaneous , Male , Middle Aged , Randomized Controlled Trials as Topic , Range of Motion, Articular , Severity of Illness Index , Spine/physiopathology , Spondylitis, Ankylosing/physiopathology , Treatment Outcome
18.
Ann Rheum Dis ; 63(1): 84-7, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14672897

ABSTRACT

OBJECTIVE: To identify clinical and immunological markers of response to treatment with infliximab in ankylosing spondylitis (AS). METHODS: Baseline and sequential cytokine levels (IL1, TNFalpha, IFNgamma, TGFbeta and IL10) were examined after 52 weeks of infliximab treatment 5 mg/kg in 22 patients. RESULTS: At week 52, 18 patients were responders and four non-responders according to ASAS group criteria. Clinical measures of disease activity between the two groups at baseline were similar, apart from a trend towards longer disease duration in non-responders (p = 0.08). Baseline CRP and TNFalpha levels were higher in responders than non-responders (p<0.01 and p<0.006, respectively). The two groups had similar baseline cytokine levels, apart from TNFalpha. Baseline CRP levels did not correlate significantly with baseline cytokine levels in responders, but a strong correlation was noted between baseline CRP and IL1, IFNgamma, and IL10 in non-responders. Apart from an early rise in TGFbeta and a decrease in IL10 in responders after the first infusion, sequential cytokine analysis for the first six months of treatment was not related to clinical disease activity measures. CONCLUSION: Although sequential cytokine analysis does not appear to be informative, baseline CRP and TNFalpha levels are useful markers of clinical response patterns in patients with AS treated with infliximab.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Cytokines/blood , Spondylitis, Ankylosing/drug therapy , Adult , Analysis of Variance , Biomarkers/blood , C-Reactive Protein/metabolism , Drug Monitoring/methods , Female , Follow-Up Studies , Humans , Infliximab , Male , Middle Aged , Patient Selection , Prognosis , Spondylitis, Ankylosing/blood , Spondylitis, Ankylosing/immunology , Treatment Outcome , Tumor Necrosis Factor-alpha/metabolism
19.
Rheumatology (Oxford) ; 43(2): 148-55, 2004 Feb.
Article in English | MEDLINE | ID: mdl-12949256

ABSTRACT

OBJECTIVE: Using humoral immune responses, Klebsiella pneumoniae has been implicated as a candidate microbial trigger in ankylosing spondylitis (AS) by several investigators but refuted by others. The objective of this case-control study was to compare the cellular (T-cell proliferation) and humoral (IgG and IgA, by ELISA) immune responses of affected individuals in multiplex AS families with those of unaffected family members and normal healthy controls in order to find out whether affected individuals exhibit a predominant immune response to K. pneumoniae. METHODS: Twenty-five families with two or more individuals affected with AS and 34 normal healthy controls matched with the affected family members for age, sex and ethnicity were enrolled in the study. All affected (n = 57) and unaffected (n = 37) family members had a detailed clinical evaluation. Peripheral blood was drawn to determine T-lymphocyte proliferation and the IgG and IgA (by ELISA analysis) immune responses to K. pneumoniae, Salmonella typhimurium, Yersinia enterocolitica and Chlamydia trachomatis. Immune responses to each of the four candidate organisms were compared in affected and unaffected individuals. Each individual was classified by the predominant antigenic immune response that they showed when comparison was made among the same concentrations of the four candidate microbial antigens. This stratification was then used (i) to compare immune responses in affected and unaffected family members and (ii) to compare clinical characteristics of affected family members. RESULTS: There was no difference in mean stimulation indices or antibody responses between affected and unaffected family members for each of the candidate organisms. In terms of predominant cellular immune responses to these organisms, there was no difference between affected and unaffected family members with respect to K. pneumoniae, C. trachomatis or Y. enterocolitica. However, a higher percentage of affected family members (25.9%) exhibited a predominant response to S. typhimurium compared with unaffected family members (5.9%, P < 0.02). In assessing antibody titres, K. pneumoniae was the predominant amongst these four organisms, but there was no difference between affected family members, unaffected family members and normal healthy controls. There was no relationship between immune responses and clinical characteristics. CONCLUSION: Our analysis of affected and unaffected family members in familial AS demonstrated no significant differences with respect to cellular or humoral immune responses to K. pneumoniae and three control microbes. In addition, K. pneumoniae did not exhibit a predominant immune response in affected individuals. Thus we find no supportive evidence to implicate a causal role for K. pneumoniae in familial AS.


Subject(s)
Klebsiella Infections/immunology , Klebsiella pneumoniae/immunology , Spondylitis, Ankylosing/microbiology , Adult , Aged , Antibodies, Bacterial/biosynthesis , Case-Control Studies , Female , Humans , Immunity, Cellular , Immunoglobulin A/biosynthesis , Immunoglobulin G/biosynthesis , Lymphocyte Activation/immunology , Male , Middle Aged , Spondylitis, Ankylosing/genetics , Spondylitis, Ankylosing/immunology , Statistics as Topic , T-Lymphocytes/immunology
20.
BJU Int ; 90(9): 872-5, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12460348

ABSTRACT

OBJECTIVE: To determine the agreement between on-table weighing and the ethanol breath test in measuring the fluid absorption of patients during transurethral prostatectomy (TURP), and to assess the practicality of on-table weighing in the clinical setting. PATIENTS AND METHODS: The absorption of irrigating fluid by the patient during TURP can lead to adverse sequelae, including cardiac stress. Despite modern techniques irrigant may still be absorbed and therefore methods to detect absorption are important. Most methods are impractical or inaccurate, but the expired ethanol technique and continuous on-table weighing are more promising. TURP was undertaken in 44 men (mean age 71 years) using continuous flow 1.5% glycine/1% ethanol as the irrigating solution. Intraoperative irrigant absorption was calculated by the ethanol breath test, using published formulae. Absorption measured by the weighing machine was calculated as (weight gain + blood loss - fluid given), and blood loss by the Hemocue method. RESULTS: The mean (sd) resected weight was 23 (14) g at a mean resection rate of 0.74 g/min. The mean (range) absorption using the balance was 456 (- 343 to 2486) mL, and using the ethanol breath test was 435 (44-2750) mL, with the mean of the differences being - 17 mL, with a 95% confidence interval (CI) of - 81 to -40, the 95% limits of agreement being - 389 to 356 mL (95% CI - 458 to - 337 and 297 to 418 mL). CONCLUSIONS: Both methods are comparable and measure irrigating fluid absorption to levels of accuracy that are useful clinically. Either method could (and should) be used in routine practice.


Subject(s)
Body Weight , Breath Tests/methods , Ethanol/analysis , Solvents/analysis , Therapeutic Irrigation/adverse effects , Transurethral Resection of Prostate/adverse effects , Absorption , Aged , Aged, 80 and over , Blood Loss, Surgical , Ethanol/pharmacokinetics , Humans , Male , Middle Aged , Postoperative Complications/etiology , Prostatic Diseases/metabolism , Prostatic Diseases/surgery , Sensitivity and Specificity , Solvents/pharmacokinetics
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