Roger D. Sturrock

ASAS/EULAR recommendations for the management of ankylosing spondylitis

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.

The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis.

Interleukin 15 (IL–15) is a novel cytokine with interleukin–2–like activity. It is also a potent T–lymphocyte chemoattractant. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the presence of activated T lymphocytes, macrophages and synoviocytes in the synovial membrane. The mechanisms of T–cell activation in RA are currently unclear. We report the presence of high concentrations of IL–15 in rheumatoid arthritis (RA) synovial fluid and have demonstrated its expression in the synovial membrane lining layer by immunohistochemistry. RA synovial fluids were found to contain chemotactic activity, which was attributable in part to the presence of IL–15. Moreover, in a murine model, injection of recombinant IL–15 was found to induce a local tissue inflammatory infiltrate consisting predominantly of T lymphocytes. Synovial fluid T lymphocytes proliferate in response to IL–15, demonstrating that continued responsiveness to IL–15 is a feature of T cells after entry into the synovial compartment. These data suggest that IL–15 can recruit and activate T lymphocytes into the synovial membrane, thereby contributing to RA pathogenesis.

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal

Objective: Non-radiographic axial spondyloarthritis (SpA) is characterised by a lack of definitive radiographic sacroiliitis and is considered an early stage of ankylosing spondylitis. The objective of this study was to develop candidate classification criteria for axial SpA that include patients with but also without radiographic sacroiliitis. Methods: Seventy-one patients with possible axial SpA, most of whom were lacking definite radiographic sacroiliitis, were reviewed as “paper patients” by 20 experts from the Assessment of SpondyloArthritis international Society (ASAS). Unequivocally classifiable patients were identified based on the aggregate expert opinion in conjunction with the expert-reported level of certainty of their judgement. Draft criteria for axial SpA were formulated and tested using classifiable patients. Results: Active sacroiliitis on magnetic resonance imaging (MRI) (odds ratio 45, 95% CI 5.3 to 383; p<0.001) was strongly associated with the classification of axial SpA. The knowledge of MRI findings led to a change in the classification of 21.1% of patients. According to the first set of candidate criteria (sensitivity 97.1%; specificity 94.7%) a patient with chronic back pain is classified as axial SpA in the presence of sacroiliitis by MRI or x rays in conjunction with one SpA feature or, if sacroilitiis is absent, in the presence of at least three SpA features. In a second set of candidate criteria, inflammatory back pain is obligatory in the clinical arm (sensitivity 86.1%; specificity 94.7%). Conclusion: The ASAS group has developed candidate criteria for the classification of axial SpA that include patients without radiographic sacroiliitis. The candidate criteria need to be validated in an independent international study.

Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy

Objective: To compare ultrasonography (US) with clinical examination in the detection of entheseal abnormality of the lower limb in patients with spondyloarthropathy (SpA). Methods: 35 patients with SpA (ankylosing spondylitis 27; psoriatic arthritis 7; reactive arthritis 1) underwent independent clinical and ultrasonographic examination of both lower limbs at five entheseal sites—superior pole and inferior pole of patella, tibial tuberosity, Achilles tendon, and plantar aponeurosis. US was performed using an ATL (Advanced Technology Laboratories, Bothell, Washington, USA) high definition imaging 3000 machine with linear 7–4 MHz and compact linear 10–5 MHz probes to detect bursitis, structure thickness, bony erosion, and enthesophyte (bony spur). An enthesitis score was formulated from these US findings giving a possible maximum total score of 36. Results: On clinical examination 75/348 (22%) entheseal sites were abnormal and on US examination 195/348 (56%) sites were abnormal. In 19 entheseal sites with bursitis on US, only five were detected by clinical examination. Compared with US, clinical examination had a low sensitivity (22.6%) and moderate specificity (79.7%) for the detection of enthesitis of the lower limbs. There was no significant correlation between the US score of enthesitis and acute phase parameters such as erythrocyte sedimentation rate (ESR) or C reactive protein (CRP). The intraobserver κ value for analysis of all sites was 0.9. Conclusions: Most entheseal abnormality in SpA is not detected at clinical examination. US is better than clinical examination in the detection of entheseal abnormality of the lower limbs in SpA. A quantitative US score of lower limb enthesitis is proposed but further studies are required to validate it in SpA.

Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double blind placebo controlled study.

In rheumatoid arthritis (RA) benefit from non-steroidal anti-inflammatory drugs (NSAIDs) is mediated through inhibition of the cyclo-oxygenase enzyme, thereby decreasing production of the 2 series prostaglandins (PGs). The lipoxygenase enzyme is intact, however, allowing leucotriene (LT) production, e.g., LTB4 (an inflammatory mediator). Treatment with evening primrose oil (EPO) which contains gamma-linolenic acid (GLA) leads to production of the 1 series PGs, e.g., PGE1, which has less inflammatory effects. Also LT production is inhibited. Eicosapentaenoic acid (EPA, fish oil) treatment provides a substrate for PGs and LTs, which are also less inflammatory. In this study 16 patients with RA were given 540 mg GLA/day (EPO), 15 patients 240 mg EPA and 450 mg GLA/day (EPO/fish oil), and 18 patients an inert oil (placebo). The aim of this study was to determine if EPO or EPO/fish oil could replace NSAID treatment in RA. The initial 12 month treatment period was followed by three months of placebo for all groups. Results at 12 months showed a significant subjective improvement for EPO and EPO/fish oil compared with placebo. In addition, by 12 months the patients receiving EPO and EPO/fish oil had significantly reduced their NSAIDs. After 3 months of placebo those receiving active treatment had relapsed. Despite the decrease in NSAIDs, measures of disease activity did not worsen. It is suggested that EPO and EPO/fish oil produce a subjective improvement and allow some patients to reduce or stop treatment with NSAIDs. There is, however, no evidence that they act as disease modifying agents.

Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis.

OBJECTIVE--To determine the prevalence of vertebral compression fractures due to osteoporosis in patients with ankylosing spondylitis. DESIGN--Prospective study of 111 consecutive patients; patients with vertebral compression fractures were entered into a case-control study. SETTING--Outpatient clinic at the centre for rheumatic diseases, Glasgow. PATIENTS--111 Consecutive patients with ankylosing spondylitis. Patients with compression fractures were matched for age and sex with two controls selected from the rest of the group. Patients with biconcave vertebral fractures were also studied. MAIN OUTCOME MEASURES--Assessments of spinal deformity and mobility and analysis of lateral radiographs of spines for presence of syndesmophytes. RESULTS--Fifteen patients with compression fractures and five with biconcave fractures were studied. Compared with the controls the patients with compression fractures had increased formation of syndesmophytes in the lumbar spine, whereas those with biconcave fractures had increased formation throughout the spine. Patients with compression fractures also had a greater degree of spinal deformity (distance from wall to tragus 24.5 cm v 12.7 cm in controls), less spinal mobility (20 v 45.6 degrees of flexion), and reduced chest expansion (2 cm v 3cm). CONCLUSION--Vertebral compression fractures due to osteoporosis are a common but frequently unrecognised complication of ankylosing spondylitis and may contribute to the pathogenesis of spinal deformity and back pain.

Global prevalence of ankylosing spondylitis

OBJECTIVES For effective health care provision, knowledge of disease prevalence is paramount. There has been no systematic endeavour to establish continent-based AS estimates, however, prevalence is thought to vary by country and background HLA-B27 prevalence. This study aimed to estimate AS prevalence worldwide and to calculate the expected number of cases. METHODS A systematic literature search was conducted. Prevalence data were extracted and used to calculate the mean prevalence by continent and the expected number of cases based on country-specific prevalence (or, if missing, the prevalence from neighbouring countries). A second estimate was made using the prevalence from countries with similar HLA-B27 prevalences if a country-specific prevalence estimate was not available. RESULTS The mean AS prevalence per 10,000 (from 36 eligible studies) was 23.8 in Europe, 16.7 in Asia, 31.9 in North America, 10.2 in Latin America and 7.4 in Africa. Additional estimates, weighted by study size, were calculated as 18.6, 18.0 and 12.2 for Europe, Asia and Latin America, respectively. There were sufficient studies to estimate the number of cases in Europe and Asia, calculated to be 1.30-1.56 million and 4.63-4.98 million, respectively. CONCLUSION This study represents the first systematic attempt to collate estimates of AS prevalence into a single continent-based estimate. In addition, the number of expected cases in Europe and Asia was estimated. Through reviewing the current literature, it is apparent that the continuing conduct of epidemiological studies of AS prevalence is of great importance, particularly as diagnostic capabilities improve and with the recent development of the criteria for axial SpA.

Enteroscopic diagnosis of small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs

15 patients with rheumatoid arthritis who were receiving non-steroidal anti-inflammatory drugs (NSAIDs) and who had chronic occult gastrointestinal bleeding underwent extended small bowel examination with a Sonde enteroscope. 7 patients (47%) were found to have jejunal or ileal ulceration. Small bowel enteroscopy may be a valuable technique for the investigation of undiagnosed gastrointestinal bleeding.

Cardiovascular risk parameters in men with ankylosing spondylitis in comparison with non-inflammatory control subjects: relevance of systemic inflammation

Men with AS (ankylosing spondylitis) are at elevated risk for CHD (coronary heart disease) but information on risk factors is sparse. We compared a range of conventional and novel risk factors in men with AS in comparison with healthy controls and, in particular, determined the influence of systemic inflammation. Twenty-seven men with confirmed AS and 19 controls matched for age were recruited. None of the men was taking lipid-lowering therapy. Risk factors inclusive of plasma lipids, IL-6 (interleukin-6), CRP (C-reactive protein), vWF (von Willebrand factor), fibrin D-dimer, ICAM-1 (intercellular cell-adhesion molecule-1) and fibrinogen were measured, and blood pressure and BMI (body mass index) were determined by standard techniques. A high proportion (70%) of men with AS were smokers compared with 37% of controls (P = 0.024). The AS patients also had a higher BMI. In analyses adjusted for BMI and smoking, men with AS had significantly higher IL-6 and CRP (approx. 9- and 6-fold elevated respectively; P < 0.001), fibrinogen (P = 0.013) and vWF (P = 0.008). Total cholesterol and HDL-C (high-density lipoprotein cholesterol) were lower (P < 0.05 and P = 0.073 respectively) in AS and thus the ratio was not different. Pulse pressure was also significantly higher in AS (P = 0.007). Notably, adjustment for IL-6 and CRP levels rendered all case-control risk factor differences, except pulse pressure, non-significant. In accordance with this finding, IL-6 correlated positively (r = 0.74, P < 0.001) with fibrinogen, but negatively (r = -0.46, P = 0.016) with total cholesterol concentration. In conclusion, men with AS have perturbances in several CHD risk factors, which appear to be driven principally by systemic inflammatory mediators. Inflammation-driven atherogenesis potentially contributes to the excess CHD risk in AS.

Free radical pathology in chronic arterial disease

The generation of toxic oxygen metabolites is more usually associated with inflammation. However, pathological free radical reactions can cause tissue damage by adversely affecting prostacyclin (PGI2) synthesis allowing initiation of coagulation. We have assessed changes in the red cell defence to toxic oxygen metabolite generation, viz measurement of glutathione concentration (GSH) and superoxide dismutase activity (SOD). GSH and SOD were measured in 20 patients with peripheral arterial disease, 22 patients with vasculitis, and 11 patients with angina, and compared to 17 matched controls. The 53 subjects with arterial disease had significantly lower SOD levels: in contrast GSH levels were significantly higher. Extracellularly plasma thiol levels (PSH) were low and caeruloplasmin (Cp) levels were high. We suggest that free radical pathology exists not only in inflammatory vascular disease but also in atherosclerosis.