Fatigue in patients with rheumatic and musculoskeletal diseases: a scoping review on definitions, measurement instruments, determinants, consequences and interventions.

OBJECTIVES: To scope published reviews addressing fatigue in rheumatoid arthritis (RA), spondyloarthritis, osteoarthritis and fibromyalgia in areas relevant for clinical practice: (1) definition, (2) measurement instruments and diagnosis, (3) determinants, (4) consequences and (5) effectiveness of interventions. METHODS: A systematic literature search of reviews was performed in five bibliographical databases. A hierarchical data extraction was applied based on review type (Cochrane reviews (CRs), followed by non-Cochrane systematic reviews (SRs) and narrative reviews (NRs)) and year of publication. Extracted data were summarised in elaborated narrative syntheses. Results were discussed with a patient panel. RESULTS: One hundred and thirty-four reviews were included (19 CRs, 44 SRs, 71 NRs). No agreed on definition was reported for general fatigue, nor for types of fatigue. Twenty-five measurement instruments were found, all self-reported. Five instruments proposed a threshold for excessive fatigue. Pain, physical function and depressive symptoms were the most frequently studied disease-related determinants of fatigue; female sex and stress the most frequent contextual determinants. Work performance, followed by impact on pain, physical activity and social roles were the most frequently studied consequences. Whenever quantified, associations between fatigue with determinants and consequences were on average small. For non-pharmacological interventions, if effect sizes were reported, these were negligible to small and for pharmacological interventions negligible to moderate. Patients recommended actions for research and practice. CONCLUSION: Syntheses of reviews point to the complexity of fatigue. The extensive amount of evidence could be used to offer tailored management plans to patients in clinical practice and inform future research agendas.

Development of a web-based decision aid for initiating biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in axial spondyloarthritis.

OBJECTIVES: To develop a web-based evidence-based decision aid to support shared decision-making in patients with axial spondyloarthritis (axSpA) who face a treatment decision to initiate or switch a biological or targeted synthetic disease modifying antirheumatic drug (b/tsDMARDs). METHODS: Through an iterative process, we systematically developed a decision aid based on evidence from the literature, explorative needs assessment interviews among patients and care providers, and input from experts of the SpA working group of the Dutch Society for Rheumatology and professionals on patient information employed at the Dutch Arthritis Society. The usability, ease of use and feasibility of the pilot version were tested among stakeholders and feedback was used to adapt the decision aid. Finally, a multifaceted strategy was used to introduce the decision aid in clinical practice. RESULTS: The decision aid consists of (1) consultation support instructions in the context of disease control and treatment needs, (2) an overview of available treatment options for axSpA, (3) detailed information on b/tsDMARDs and an interactive option grid that facilitates comparison of characteristics and (4) a final check supporting patients to deliberate on the decision to initiate or switch a b/tsDMARD. Rheumatologists introduced the decision aid in several Dutch rheumatology settings and the Dutch Arthritis Society posted it on their website, social media and in their monthly newsletter. CONCLUSION: We developed an evidence-based decision aid to support axSpA patients who face a treatment decision to initiate or switch a b/tsDMARD and introduced this in clinical practice.

Gastrointestinal Adverse Drug Reaction Profile of Etanercept: Real-world Data From Patients and Healthcare Professionals.

OBJECTIVE: We aimed to describe the nature and frequency of gastrointestinal adverse drug reactions (GI-ADRs) of etanercept (ETN) using patient-reported and healthcare professional (HCP)-registered data and compared this frequency with the GI-ADR frequency of the widely used tumor necrosis factor-α inhibitor adalimumab (ADA). METHODS: Reported GI-ADRs of ETN for rheumatic diseases were collected from the Dutch Biologic Monitor and DREAM registries. We described the clinical course of GI-ADRs and compared the frequency with ADA in both data sources using Fisher exact test. RESULTS: Out of 416 patients using ETN for inflammatory rheumatic diseases in the Dutch Biologic Monitor, 25 (6%) patients reported 36 GI-ADRs. In the DREAM registries 11 GI-ADRs were registered for 9 patients (2.3%), out of 399 patients using ETN, with an incidence of 7.1 per 1000 patient-years. Most GI-ADRs consisted of diarrhea, nausea, and abdominal pain. GI-ADRs led to ETN discontinuation in 1 patient (4%) and dose adjustment in 4 (16%) in the Dutch Biologic Monitor. Eight GI-ADRs (73%) led to ETN discontinuation in the DREAM registries. The frequency of GI-ADRs of ETN did not significantly differ from GI-ADRs of ADA in both data sources (Dutch Biologic Monitor: ETN 8.7% vs ADA 5.3%, P = 0.07; DREAM: ETN 2.8% vs ADA 4.7%, P = 0.16). CONCLUSION: Most GI-ADRs associated with ETN concerned gastrointestinal symptoms. These ADRs may lead to dose adjustment or ETN discontinuation. The frequency of ETN-associated GI-ADRs was comparable to the frequency of ADA-associated GI-ADRs. Knowledge about these previously unknown ADRs can facilitate early recognition and improve patient communication.

Infliximab treatment reduces depressive symptoms in patients with ankylosing spondylitis: an ancillary study to a randomized controlled trial (ASSERT).

BACKGROUND: Patients with ankylosing spondylitis (AS) are at increased risk of depression. This increased risk has been hypothesized to be solely secondary due to AS-related symptoms, or additionally due to a common inflammatory pathway. From a clinical perspective, it is important to know whether treatment with tumor necrosis factor alpha inhibitors reduces depressive symptoms, while from a pathophysiological point of view, it would be insightful to understand whether such an effect would be a direct result of reduced inflammation, the result of reduced AS-related symptoms, or both. The objective of this study was to evaluate the effect of infliximab on depressive symptoms in patients with AS in a randomized-controlled trial setting. METHODS: Data were retrieved from a subgroup of patients from the AS Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT). Patients were randomly allocated to infliximab (n = 16) or placebo (n = 7) until week 24, after which all received infliximab until week 54. Associations between treatment group and depressive symptoms, measured with the Center for Epidemiological Studies Depression scale (CES-D, range 0-60 (best-worst)) at baseline and over time, were explored with generalized estimating equations (GEE). RESULTS: Mean CES-D score at baseline was 15.5 (SD 9.3) in the infliximab group and 17.3 (SD 5.7) in the placebo group. Twelve patients (52%) had a CES-D score > 16, suggestive for clinical depression. After 24 weeks, mean CES-D had decreased to 9.5 (SD 11.4) in the infliximab group, but was 18.0 (SD 6.9) in the placebo group. GEE revealed larger improvements in depressive symptoms (B = - 6.63, 95%CI - 13.35 to 0.09) and odds of possible depression (OR = 0.02, 95%CI 0.00 to 0.72) in the infliximab group, compared to the placebo group. Both associations largely disappeared when adjusted for self-reported disease activity and/or physical function. Additional adjustment for C-reactive protein (CRP) did not change results. CONCLUSIONS: Depressive symptoms are common in patients with AS and active disease. Infliximab improves these depressive symptoms in AS when compared to placebo by improving disease symptoms. We did not find an indication for a direct link between CRP-mediated inflammation and depressive symptoms. TRIAL REGISTRATION: Trial registration (ASSERT): NCT00207701 . Registered on September 21, 2005 (retrospectively registered).

Development and Validation of a Patient-reported Score to Screen for Mucosal Inflammation in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Patient-reported outcome measures [PROMs] assessing inflammatory bowel disease [IBD] activity are of interest for monitoring in clinical practice, telemedicine systems, or trials. Different PROMs for follow-up of disease activity are available; however, none was developed with endoscopy as gold standard. The objective of this study was to develop and validate a PROM to predict endoscopic disease activity, following the recommendations of the Food and Drug Administration. METHODS: During development, 178 IBD patients undergoing a colonoscopy were asked to fill out 13 clinical questions derived from the literature. During endoscopy, inflammation was assessed with the simplified endoscopic score for Crohn's disease [CD] and the Mayo endoscopic subscore for ulcerative colitis [UC]. Based on correlation with endoscopic inflammation, questions were reduced to a total of six for CD and five for UC. The newly developed Monitor IBD At Home questionnaire [MIAH] was validated in an independent cohort of 135 CD and 131 UC patients. Additionally, diagnostic accuracy of the MIAH combined with a calprotectin home test [CHT] was assessed. RESULTS: The MIAH-CD includes questions on rectal bleeding, mucus, stool frequency, urgency, fatigue, and patient-reported disease activity. The MIAH-UC contains items on rectal bleeding, stool frequency, urgency, abdominal pain, and patient-reported disease activity. Both questionnaires showed to be valid, reliable, and responsive to changes. The MIAH and CHT combined had a sensitivity, specificity, negative predictive value [NPV], and positive predicitive value [PPV] of 96.7%, 66.7%, 94.7%, and 76.3% for CD and of 88.2%, 81.4%, 95.6%, and 60.0% for UC, respectively, compared with endoscopy. CONCLUSIONS: The MIAH is the first PROM developed to predict endoscopic inflammation in IBD patients. A combination of this questionnaire and a CHT shows excellent diagnostic accuracy to screen for patients who need further assessment of disease activity, and can be used in daily practice, telemedicine systems, and trials.

Treatment patterns, unmet need, and impact on patient-reported outcomes of psoriatic arthritis in the United States and Europe.

Psoriatic arthritis (PsA) is a chronic, inflammatory disease. The effects of PsA real-world treatment patterns on patient-reported outcomes in the US and 5 European countries (EU5; France, Germany, Italy, Spain, UK) were evaluated. Respondents from the 2016 National Health and Wellness Survey received advanced therapies (e.g., biologic disease-modifying antirheumatic drugs [DMARDs]), other therapies, (e.g., conventional synthetic DMARDs), or no treatment. Assessments included demographics, disease severity (patient-reported), comorbidities (Charlson Comorbidity Index), health status (Short Form-36 Health Survey), depression (Patient Health Questionnaire-9), work productivity (Work Productivity and Activity Index), and treatment adherence (Morisky Medication Adherence Scale-8). Overall, 1037 respondents from the US and 947 respondents from the EU5 were included. Of these, 21.7% US and 7.3% EU5 respondents received advanced therapies; 16.6% and 28.5%, other therapies; and 61.7% and 64.2%, no treatment, respectively. During treatment with advanced or other therapies, 40.8-54.7% US and 57.7-58.9% EU5 respondents self-reported moderate or severe PsA. Respondents receiving advanced therapies had the highest Charlson Comorbidity Index score (US, 1.25; EU5, 1.42); the lowest scores were with no treatment (0.52 and 0.49, respectively). Employment was lowest with other therapies (US, 47.7%; EU5, 41.1%). Overall work impairment was reported by 57.9% US and 62.6% EU5 respondents receiving advanced therapies. Medication adherence was generally low in the US and medium in the EU5 (Morisky Medication Adherence Scale-8: low, US 40.1-46.7%, EU5, 29.0-35.2%; medium, US 29.3-36.1%, EU5 37.8-49.3%; high, US 23.8-24.0%; EU5, 21.7-27.0%). Advanced and other therapies reduced PsA severity; however, > 40% of respondents reported moderate or severe PsA during treatment. Better management and adherence may reduce unmet need and disease burden. Further work is required to improve PsA diagnosis and time to treatment initiation.

Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study.

OBJECTIVES: We explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development. METHODS: Individuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo. RESULTS: Eighty-one individuals received treatment and were followed up for a mean of 29.0 (0-54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development. CONCLUSIONS: A single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.

Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis.

OBJECTIVES: To evaluate construct validity, interpretability, reliability and responsiveness as well as determination of cut-off points for good and poor health within the original English version and the 18 translations of the disease-specific Assessment of Spondyloarthritis international Society Health Index (ASAS HI) in 23 countries worldwide in patients with spondyloarthritis (SpA). METHODS: A representative sample of patients with SpA fulfilling the ASAS classification criteria for axial (axSpA) or peripheral SpA was used. The construct validity of the ASAS HI was tested using Spearman correlation with several standard health outcomes for axSpA. Test-retest reliability was assessed by intraclass correlation coefficients (ICCs) in patients with stable disease (interval 4-7 days). In patients who required an escalation of therapy because of high disease activity, responsiveness was tested after 2-24weeks using standardised response mean (SRM). RESULTS: Among the 1548 patients, 64.9% were men, with a mean (SD) age 42.0 (13.4) years. Construct validity ranged from low (age: 0.10) to high (Bath AnkylosingSpondylitisFunctioning Index: 0.71). Internal consistency was high (Cronbach's α of 0.93). The reliability among 578 patients was good (ICC=0.87 (95% CI 0.84 to 0.89)). Responsiveness among 246 patients was moderate-large (SRM=-0.44 for non-steroidal anti-inflammatory drugs, -0.69 for conventional synthetic disease-modifying antirheumatic drug and -0.85 for tumour necrosis factor inhibitor). The smallest detectable change was 3.0. Values ≤5.0 have balanced specificity to distinguish good health as opposed to moderate health, and values ≥12.0 are specific to represent poor health as opposed to moderate health. CONCLUSIONS: The ASAS HI proved to be valid, reliable and responsive. It can be used to evaluate the impact of SpA and its treatment on functioning and health. Furthermore, comparison of disease impact between populations is possible.

Is radiographic progression in radiographic axial spondyloarthritis related to matrix metalloproteinase degradation of extracellular matrix?

BACKGROUND: Radiographic axial spondyloarthritis (r-axSpA) is associated with extracellular matrix (ECM) remodelling of affected tissues. We investigated whether there was a relationship between biomarkers of ECM remodelling and 2-year radiographic progression in r-axSpA. METHODS: Patients from the Outcome in Ankylosing Spondylitis International Study (OASIS) were included if they had serum, clinical and spinal radiographic assessments available at baseline and 2 years later. Two readers independently scored the radiographs according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The average score was used. Type I, V and VI collagen metabolites (C1M, C5M and C6M) and citrullinated and matrix metalloproteinase-degraded vimentin (VICM) were assessed in serum by ELISAs. The relationship between serum biomarkers and 2-year radiographic progression was investigated using linear regression analyses adjusted for potential confounders. Interactions were tested. RESULTS: Patients included (n=122) had a mean age of 45 years (SD 12), 70% were male and 82% were human leucocyte antigen-B27 positive. The mean 2-year mSASSS progression was 2.1 (2.9) units. Only C1M was significantly associated with mSASSS progression (ß=0.01, 95% CI 0.00 to 0.03). The effect disappeared after adjustment for confounders. C5M, C6M and VICM showed no relationship with mSASSS progression. CONCLUSION: We did not find evidence that degradation of ECM is related to radiographic progression in patients with r-axSpA.

Exploring conditions for redistribution of anti-tumor necrosis factors to reduce spillage: A study on the quality of anti-tumor necrosis factor home storage.

BACKGROUND AND AIM: Biologicals are potent drugs for immune-mediated inflammatory diseases. After discontinuation or switch of therapy, many patients have unused biological injectors left. This study aimed to evaluate potential redistribution of unused injectors to prevent spillage of these costly drugs by assessing (i) the quality of transport and home storage through the proportion of injectors stored within the recommended temperature range (2-8 °C) and (ii) acceptance of redistribution by patients. METHODS: All golimumab users, irrespective of the indication, at Maastricht University Medical Center were eligible for inclusion. Patients received golimumab in a sealed bag containing a validated temperature sensor, measuring temperature every 5 min. Patients were asked to store their medication as usual. Deviations from the recommended range were defined as any duration below 0 °C and > 30 min below 2 °C or above 8 °C. After 3 months, patients completed a questionnaire on their opinion towards potential redistribution of unused biologicals. RESULTS: Fifty patients (42.0% male, mean age 53.2 ± 14.3 years) received 276 injectors. The mean storage time was 30.9 ± 33.1 days. Only 11.6% of the injectors were stored within the recommended temperature range. In addition, 11.2% were stored > 30 min below 0 °C and 33.2% were stored > 1 week above 8 °C. Of all patients, 95% would accept redistributed medication when product quality is ensured. CONCLUSIONS: During transport and home storage, only one in eight biological injectors was stored within the recommended temperature range. This hinders redistribution of unused injectors but also raises concern regarding drug effectiveness in immune-mediated inflammatory disease patients.

Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study.

OBJECTIVES: There is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants. METHODS: CRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 µg/mL). RESULTS: Sixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0-49.4] µg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 µg/mL), and 1 had a minimal CZP level of 0.042 µg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 µg/mL). CONCLUSIONS: There was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary. TRIAL REGISTRATION NUMBER: NCT02019602; Results.

Global Prevalence of Spondyloarthritis: A Systematic Review and Meta-Regression Analysis.

OBJECTIVE: To summarize the prevalence of spondyloarthritis (SpA) and its subtypes in the general population, and to identify demographic and methodologic characteristics that might explain heterogeneity in prevalence estimates. METHODS: A systematic literature search was performed to identify relevant articles. Risk of bias was assessed and data were extracted. Pooled prevalences were calculated. Potential sources of heterogeneity were explored by subgroup analysis and meta-regression analysis. RESULTS: The prevalence of SpA ranged from 0.20% (95% confidence interval [95% CI] 0.00-0.66) in South-East Asia to 1.61% (95% CI 1.27-2.00) in Northern Arctic communities; the prevalence of ankylosing spondylitis (AS) from 0.02% (95% CI 0.00-0.21) in Sub-Saharan Africa to 0.35% (95% CI 0.24-0.48) in Northern Arctic communities; and the prevalence of psoriatic arthritis (PsA) from 0.01% (95% CI 0.00-0.17) in the Middle East to 0.19% (95% CI 0.16-0.32) in Europe. The following characteristics were significantly associated with variation in prevalence of SpA, AS, and/or PsA: proportion of females, mean age of the sample, geographic area and setting (demographic characteristics), year of data collection, case finding, and case ascertainment (methodologic characteristics). For the other SpA subgroups, too few studies were available to conduct a meta-analysis, but prevalence estimates of reactive arthritis (range 0.0-0.2%), SpA related to inflammatory bowel disease (range 0.0-0.1%), and undifferentiated SpA (range 0.0-0.7%) were generally low. CONCLUSION: SpA is a common disease, but with large variation in reported prevalence estimates, which can partly be explained by differences in demographic and methodologic characteristics. Particularly, geographic area as well as case finding account for a substantial part of the heterogeneity.

Do patients with ankylosing spondylitis adapt to their disease? Evidence from a 'then-test' in patients treated with TNF inhibitors.

OBJECTIVE: To investigate whether patients with ankylosing spondylitis (AS) adapt to their disease, using the 'then-test'. METHODS: Data from patients participating in the AS Study for Evaluation of Recombinant Infliximab Therapy (ASSERT) and continuing in the European AS Infliximab Cohort (EASIC) were used. At 5 assessments in EASIC, patients were asked to rerate their global well-being before the start of infliximab in ASSERT. The patients evaluated their past situation by using a 'then-test' ('retrospective patient global'). Initial and retrospective patient global were compared using a paired t test, and mixed linear models investigated whether the retrospective score of well-being was stable at all follow-up assessments in EASIC. Linear regression analysis explored whether treatment response was associated with the difference between the initial and retrospective score ('gap') while adjusting for possible confounders. RESULTS: 86 patients (mean age 39.8 years (SD=10.4), mean disease duration 10.8 years (SD=8.5)) contributed to the current analyses. At the time of starting infliximab, patients judged their global at 7.0 (SD=1.6), and with the 'then-test' at 7.2 (SD=2.3) (p=0.45). Time elapsed did not influence the 'then-test' (p=0.13). Multivariably, the gap was irrespective of treatment response, but associated with initial patient global (p<0.01) and initial Bath AS Disease Activity Index (p=0.02). CONCLUSIONS: Patients with AS accurately judged their global well-being before starting treatment with tumour necrosis factor inhibition, even though substantial time had elapsed. The difference between initial and retrospective judgment was irrespective of treatment response. In this setting, the 'then-test' could not prove adaptation in AS. TRIAL REGISTRATION NUMBER: NCT01286545.

Lifestyle factors may modify the effect of disease activity on radiographic progression in patients with ankylosing spondylitis: a longitudinal analysis.

OBJECTIVES: To investigate the complex relationship between inflammation, mechanical stress and radiographic progression in patients with ankylosing spondylitis (AS), using job type as a proxy for continuous mechanical stress. METHODS: Patients from the Outcome in Ankylosing Spondylitis International Study were followed up for 12 years, with 2-yearly assessments. Two readers independently scored the X-rays according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Disease activity was assessed by the AS Disease Activity Score C reactive protein (ASDAS-CRP). The relationship between ASDAS and spinal radiographic progression was investigated with longitudinal analysis, with job type at baseline (physically demanding ('blue-collar') versus sedentary ('white-collar') labour) as a potential factor influencing this relationship. The effects of smoking status and socioeconomic factors were also investigated. RESULTS: In total, 184 patients were included in the analyses (70% males, 83% human leucocyte antigen-B27 positive, 39% smokers, 48% blue-collar workers (65/136 patients in whom data on job type were available)). The relationship between disease activity and radiographic progression was significantly and independently modified by job type: In 'blue-collar' workers versus 'white-collar' workers, every additional unit of ASDAS resulted in an increase of 1.2 versus 0.2 mSASSS-units/2-years (p=0.014 for the difference between blue-collar and white-collar workers). In smokers versus non-smokers, every additional unit of ASDAS resulted in an increase of 1.9 versus 0.4 mSASSS-units/2-years. CONCLUSIONS: Physically demanding jobs may amplify the potentiating effects of inflammation on bone formation in AS. Smoking and socioeconomic factors most likely confound this relationship and may have separate effects on bone formation.

Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort.

OBJECTIVES: To analyse the long-term relationship between disease activity and radiographic damage in the spine in patients with ankylosing spondylitis (AS). METHODS: Patients from the Outcome in AS International Study (OASIS) were followed up for 12 years, with 2-yearly clinical and radiographic assessments. Two readers independently scored the X-rays according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Disease activity measures include the Bath AS Disease Activity Index (BASDAI), AS Disease Activity Index (ASDAS)-C-reactive protein (CRP), CRP, erythrocyte sedimentation rate (ESR), patient's global assessment and spinal pain. The relationship between disease activity measures and radiographic damage was investigated using longitudinal, autoregressive models with 2-year time lags. RESULTS: 184 patients were included (70% males, 83% HLA-B27 positive, mean (SD) age 43 (12) years, 20 (12) years symptom duration). Disease activity measures were significantly longitudinally associated with radiographic progression. Neither medication nor the presence of extra-articular manifestations confounded this relationship. The models with ASDAS as disease activity measure fitted the data better than models with BASDAI, CRP or BASDAI+CRP. An increase of one ASDAS unit led to an increase of 0.72 mSASSS units/2 years. A 'very high disease activity state' (ie, ASDAS >3.5) compared with 'inactive disease' (ie, ASDAS <1.3) resulted in an additional 2-year progression of 2.31 mSASSS units. The effect of ASDAS on mSASSS was higher in males versus females (0.98 vs -0.06 mSASSS units per ASDAS unit) and in patients with <18 years vs ≥18 years symptom duration (0.84 vs 0.16 mSASSS units per ASDAS unit). CONCLUSIONS: This is the first study showing that disease activity contributes longitudinally to radiographic progression in the spine in AS. This effect is more pronounced in men and in the earlier phases of the disease.

Bone marrow edema on magnetic resonance imaging (MRI) of the sacroiliac joints is associated with development of fatty lesions on MRI over a 1-year interval in patients with early inflammatory low back pain: a 2-year followup study.

OBJECTIVE: To assess whether bone marrow edema (BME) detected on magnetic resonance imaging (MRI) of the sacroiliac joints (MRI-SIJ) is associated with development of structural changes on both MRI and pelvic radiographs in patients with early inflammatory back pain (IBP). METHODS: Patients with IBP ≤ 2 years were followed for 2 years with annual MRI-SIJ. MRI were scored for BME and structural changes (erosions and fatty lesions). Pelvic radiographs were graded according to the modified New York (mNY) criteria. With generalized estimated equation analysis, a time trend in the structural change scores was investigated. RESULTS: Sixty-eight patients [38% male; mean (SD) age 34.9 (10.3) yrs] were included. During the 2-year followup, pelvic radiograph grading remained constant. On MRI, the number of erosions per patient increased significantly (mean score 2.5 at baseline and 3.5 at 2-yr followup; p = 0.05). A trend was found for an increase in the number of fatty lesions per patient (mean score 5.4 at baseline and 8.5 at 2-yr followup; p = 0.06). Overall, BME was associated with the development of fatty lesions (right SIJ: OR 3.13, 95% CI 1.06-9.20; left SIJ: OR 22.13, 95% CI 1.27-384.50), preferentially in quadrants showing resolution of BME. In contrast, BME (or the resolution thereof) was not associated with the development of erosions. CONCLUSION: BME at baseline, especially when it disappears over time, results in the development of fatty lesions, but an association with erosions could not be demonstrated.

Prevalence of self-reported spondyloarthritis features in a cohort of patients with inflammatory bowel disease.

BACKGROUND: Musculoskeletal symptoms belonging to the spectrum of 'seronegative spondyloarthritis' (SpA) are the most common extraintestinal manifestations in patients with inflammatory bowel disease (IBD) and may lead to important disease burden. Patients with suspected SpA should be referred to a rheumatologist for further evaluation. OBJECTIVE: To investigate the self-reported prevalence of musculoskeletal SpA features in a cohort of patients with IBD and to compare this with actual referrals to a rheumatologist. METHODS: Consecutive patients with IBD visiting the outpatient clinic were interviewed by a trained research nurse about possible SpA features using a standardized questionnaire regarding the presence or history of inflammatory back pain, peripheral arthritis, enthesitis, dactylitis, psoriasis, uveitis and response to nonsteroidal anti-inflammatory drugs. All patient files were verified for previous visits to a rheumatologist and any rheumatic diagnosis. RESULTS: At least one musculoskeletal SpA feature was reported by 129 of 350 (36.9%) patients. No significant differences between patients with Crohn disease and ulcerative colitis were found. Review of medical records showed that 66 (51.2%) patients had ever visited a rheumatologist. Axial SpA was diagnosed in 18 (27.3%) patients, peripheral SpA in 20 (30.3%) patients and another rheumatic disorder in 14 (21.2%) patients. CONCLUSION: Musculoskeletal SpA features are frequently present in patients with IBD. However, a substantial group of patients is not evaluated by a rheumatologist. Gastroenterologists play a key role in early referral of this often debilitating disease.

Combination therapy for pain management in inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis).

BACKGROUND: Despite optimal therapy with disease-modifying antirheumatic drugs, many people with inflammatory arthritis (IA) continue to have persistent pain that may require additional therapy. OBJECTIVES: To assess the benefits and safety of combination pain therapy for people with IA (rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and other spondyloarthritis (SpA)). We planned to assess differences in effects between patients on background disease-modifying antirheumatic drug (DMARD) therapy and patients on no background therapy in subgroup analyses. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; and EMBASE. We did not impose any date or language restrictions in the search. We also handsearched conference proceedings of the American College of Rheumatology and the European League against Rheumatism (2008-10). SELECTION CRITERIA: Randomised and controlled clinical trials (RCTs and CCTs) assessing combination therapy (at least two drugs from the following classes: analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, opioid-like drugs and neuromodulators (antidepressants, anticonvulsants and muscle relaxants)) compared with monotherapy, for adults with IA (RA, AS, PsA and other SpA). We speficically excluded studies that did not report pain or studies without a standardised pain scale as an outcome measure. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed risk of bias and extracted data. MAIN RESULTS: Twenty-three trials (total of 912 patients) met the inclusion criteria (22 in RA; one in a mixed population of RA and osteoarthritis); all except one were published before 1990. Most study populations were not taking DMARDs (e.g. methotrexate, sulphasalazine, hydroxychloroquine and leflunomide) and all studies were performed prior to the introduction of biologic therapies (e.g. etanercept, infliximab and adalimumab). All trials were at high risk of bias, heterogeneity precluded meta-analysis, and we were only able to report a general description of results.The majority (18 studies, 78%) found no differences between the combination and monotherapy treatments they studied, while five (22%) reported conflicting results, favouring either the combination or monotherapy arms.From the 12 trials on NSAID + analgesic vs NSAID, nine reported no significant difference between the interventions, while three did: in two, the combination therapy achieved better pain control; and the third trial compared combination therapy with two different dosages of monotherapy (NSAID alone) and reported that a high dose phenylbutazone was superior to combination therapy (paracetamol + aspirin), which was superior to low dose phenylbutazone.From the five studies on the combination of two NSAIDS vs one NSAID, four reported no significant differences between interventions, and one reported significantly better pain control with combination therapy.The single trial comparing a combination of opioid + neuromodulator vs opioid reported better pain control with monotherapy.The remaining trials (NSAID + neuromodulator vs NSAID (3 trials); opioid + NSAID vs NSAID (1 trial); and opioid + analgesic vs analgesic (1 trial)) found no significant difference between combination therapy and monotherapy.Information regarding withdrawals due to inadequate analgesia and safety was incompletely reported, but in general there were no differences between combination therapy and monotherapy.No data were available that addressed the value of combination pain therapy or monotherapy for people with IA who have optimal disease suppression. There were no studies that included patients with AS, PsA or SpA. AUTHORS' CONCLUSIONS: Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for people with IA. Importantly, there are no studies addressing the value of combination therapy for patients with IA who have persistent pain despite optimal disease suppression. Well designed trials are needed to address this question.

RAPID and FAST4WARD trials: certolizumab pegol for rheumatoid arthritis.

In the last decade, biological therapies have dramatically changed the treatment for rheumatoid arthritis (RA) in such a way that remission is currently an achievable goal. The armamentarium of therapeutic options for RA has recently been enriched with another approved anti-TNF-alpha agent, certolizumab pegol (CZP). This article reviews the trials conducted with CZP in RA, the Rheumatoid Arthritis PreventIon of structural Damage (RAPID 1 and 2) and the EFficAcy and Safety of cerTolizumab pegol - 4 Weekly dosAge in RheumatoiD arthritis (FAST4WARD). These trials have demonstrated that this new biological agent significantly improves the clinical signs and symptoms of RA, inhibits progression of structural damage, and improves physical function and quality of life in patients with active RA who have failed treatment with methotrexate. The safety profile of CZP is acceptable and similar to that of other anti-TNF-alpha agents.

Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate the effect of infliximab on progression of structural damage over 2 years in patients with ankylosing spondylitis (AS). METHODS: In the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT), a randomized, double-blind, placebo-controlled trial of the efficacy of infliximab compared with placebo, 279 patients with active AS received either placebo through week 24 and then infliximab 5 mg/kg from week 24 through week 96 (n=78) or infliximab 5 mg/kg from baseline through week 96, administered every 6 weeks after a loading dose (n=201; these patients were the focus of the radiographic analyses). Radiographic findings in patients from the ASSERT trial were indistinguishable from those in a historical control cohort of patients who had no prior use of anti-tumor necrosis factor agents (from the Outcome in Ankylosing Spondylitis International Study [OASIS] database; n=192). Radiographic progression of structural damage from baseline to the 2-year followup was scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). All images were scored in one batch. RESULTS: Median changes in the mSASSS from baseline to year 2 were 0.0 for both the OASIS and the ASSERT cohorts (P=0.541). Mean changes in the mSASSS were also similar between the OASIS and ASSERT cohorts (mean+/-SD change over 2 years 1.0+/-3.2 and 0.9+/-2.6, respectively). In addition, results from sensitivity analyses did not show a statistically significant difference in the mSASSS between the OASIS and ASSERT cohorts. CONCLUSION: AS patients who received infliximab from baseline through week 96 did not show a statistically significant difference in inhibition of structural damage progression at year 2, as assessed using the mSASSS scoring system, when compared with radiographic data from the historical control OASIS cohort. Improvements in clinical outcomes and spinal inflammation have been previously demonstrated with the use of infliximab therapy.