Dietmar Krause

Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis.

OBJECTIVE This study investigated whether efficacious methotrexate (MTX) treatment has an impact on mortality of patients with severe rheumatoid arthritis (RA). METHODS In this prospective, observational, one-center study, patients with severe RA refractory to other disease-modifying antirheumatic drugs started MTX treatment between 1980 and 1987. Patients were divided into 4 different groups according to their response to MTX treatment after 1 year (>50% improvement [n = 99], 20-50% improvement [n = 70], no improvement [n = 52], and discontinued treatment [n = 35]). After a followup of 7.5-15.3 years (mean 10 years), the numbers of deaths were assessed in the different groups. Standardized mortality ratios (SMR) were calculated by comparing the number of observed deaths in the study with the number of expected deaths in an age- and sex-matched sample of the general population. RESULTS Two hundred seventy-one patients entered the study between 1980 and 1987. In 1995/1996, outcomes for 256 patients (94.5%) could be documented; 88 patients (34.4%) had died. In patients with >50% improvement after 1 year, the SMR was 1.47, while in patients with 20-50% improvement, the SMR was 1.85. In both groups combined, the SMR was 1.64 (95% confidence interval [95% CI] 1.11-2.17), compared with 4.11 (95% CI 2.56-5.66) in patients without improvement. Patients who had discontinued MTX treatment during the first year had an SMR of 5.56 (95% CI 3.29-7.83). CONCLUSION Patients with severe RA who do not respond to MTX treatment have a poor prognosis, with >4-fold increased mortality compared with the general population, while RA patients who respond to MTX treatment have only a moderately increased mortality rate.

Do patients with non-radiographic axial spondylarthritis differ from patients with ankylosing spondylitis?

Patients with axial spondylarthritis (SpA) who have structural changes in the sacroiliac joints and/or the spine have been classified as having ankylosing spondylitis (AS), while those without such changes are now classified as having nonradiographic axial SpA (nr‐axSpA). The differentiating features are incompletely understood.

Patients with fibromyalgia rarely fulfil classification criteria for axial spondyloarthritis

Background The Assessments of Spondyloarthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA) have been criticized because of insufficient differentiation towards FM. The aim of this study was to compare the performance of currently used classification criteria in patients diagnosed with axSpA or FM. Methods Patients were prospectively included if diagnosed with axSpA or FM by the treating rheumatologist and evaluated by an independent examiner for fulfilment of the classification criteria for axSpA (ASAS criteria) and/or FM (1990 ACR classification and 2010 ACR diagnostic criteria). Patients with axSpA were stratified based on classification as non-radiographic axSpA (nr-axSpA) or AS. Symptom severity was assessed by established disease-related questionnaires. Results Overall, 300 patients were included, 100 with FM and 200 with axSpA of which 100 each had nr-axSpA and AS. Almost all FM patients fulfilled the 2010 (100%) and 1990 ACR criteria (98%) for FM, but only 2% fulfilled the ASAS criteria. When calculations were based on only the FM patients with available HLA-B27 results (n = 40), the proportion fulfilling the ASAS criteria was 5%. All axSpA patients met the ASAS criteria but also the 2010 (24%) and 1990 (13.5%) FM criteria. More patients with AS (29% and 19%) than with nr-axSpA (19% and 8%) fulfilled the 2010 and 1990 FM criteria, respectively. Conclusion FM patients only rarely fulfil classification criteria for axSpA but some axSpA patients also fulfil FM criteria. Since this was more frequent in patients with AS it may be related to the severity and duration of chronic pain in axSpA patients. Assessment instruments evaluated in axSpA are not disease-specific. The phenomenon of central pain sensitization in rheumatic diseases deserves more study.

Efficiency of treatment with non-steroidal anti-inflammatory drugs according to current recommendations in patients with radiographic and non-radiographic axial spondyloarthritis

Objective. NSAIDs are first-line therapy in axial SpA (axSpA). The proportion of patients responding to NSAIDs and differences between AS and non-radiographic axSpA (nr-axSpA) in this regard have not been studied in detail to date. The aim of this study was to examine the proportion of patients with AS and nr-axSpA responding to NSAIDs according to current treatment recommendations. Methods. Consecutive anti-TNF-naïve patients with nr-axSpA and AS (n = 50 each) were included if their BASDAI score was ⩾4 without having received maximal NSAID doses. In case of a BASDAI score ⩾4 1 week later, another NSAID was prescribed. For the next 3 weeks, continuous intake of maximal doses was recommended but patients could reduce doses in case of intolerance or improvement. MRI of the SI joints was performed at baseline and week 4. Results. All outcomes except for CRP and MRI scores improved significantly after 4 weeks of NSAIDs, with no difference between axSpA subgroups. An Assessment of SpondyloArthritis international Society 40% (ASAS40) response and partial remission rates were 35 and 16% at week 4, respectively. At the same time point, a BASDAI score ⩾4 was still present in 44% of patients, 30% of which had reduced NSAID doses, partly due to intolerance (38%). Only 13% of all patients had continuously taken NSAIDs at the maximal dosage, but there was no difference in the efficacy outcome compared with those who had taken reduced doses. Conclusion. AS and nr-axSpA patients had similar response rates to NSAIDs while objective signs of inflammation did not change over 4 weeks. Only a minority of patients was willing to take maximal doses of NSAIDs, and ⩾40% patients remained candidates for TNF blockers. These results may influence future trial designs.

The risk of peripheral artery disease in older adults - seven-year results of the getABI study

BACKGROUND To assess the risk of peripheral artery disease (PAD) in older adults and the contribution of traditional and novel risk factors to the incidence of PAD. PATIENTS AND METHODS 344 general practitioners (GPs), trained by vascular specialists all over Germany, enrolled 6,880 unselected participants aged 65 years or older (getABI study). The onset of PAD was determined by a regression method in the course of repeated measurements of the ankle brachial index (ABI) over seven years. PAD onset was defined by the declining linear regression ABI line reaching 0.9 or by PAD symptoms. RESULTS The cumulative PAD incidence over seven years was 12.9%, corresponding to an incidence rate of 20.3 per 1000 person years (95% confidence interval [95%CI] 18.8 to 21.7). Logistic regression analysis showed that traditional risk factors contributed significantly to the risk of PAD: current smoker status (odds ratio 2.65, 95%CI 2.08 to 3.37), diabetes (1.35, 95%CI 1.13 to 1.62), and low-density lipoprotein >130 mg/dl (1.26, 95%CI 1.07 to 1.48). Three novel risk factor candidates showed significant impact on PAD incidence: elevated sensitive C-reactive protein level (1.23, 95%CI 1.05 to 1.45), impaired estimated glomerular filtration rate (1.27, 95%CI 1.03 to 1.56), and elevated homocysteine level (1.19, 95%CI 1.01 to 1.41). CONCLUSIONS Older adults in Germany have a PAD risk of 12.9% per seven years. Potentially modifiable traditional PAD risk factors yield high impact on PAD incidence. Novel risk factor candidates may contribute to the risk of PAD.

Quantification of Bone Marrow Edema by Magnetic Resonance Imaging Only Marginally Reflects Clinical Neck Pain Evaluation in Rheumatoid Arthritis and Ankylosing Spondylitis

Objective. Neck pain is common in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). We investigated the correlation of bone marrow edema (BME) on magnetic resonance imaging (MRI) in RA and AS and its association with clinical complaints of neck pain. Methods. Cervical spine short-tau inversion recovery-MRI and T1w-MRI of 34 patients with RA and 6 patients with AS complaining about neck pain were obtained. Clinical and laboratory data were available. BME was scored by 2 blinded readers using a modification of a published score, including various cervical sites. Degenerative changes were also quantified. Results. Patients were predominantly women (82.5%), and mean ± SD age was 57.5 ± 11.8 years, C-reactive protein (CRP) was 0.8 ± 1.3 mg/dl, and pain score was 46.0 ± 17.5. BME was detected in 24/40 patients (60%) involving the atlantoaxial region (21%), vertebral bodies (75%), facet joints (29%), and spinous processes (46%). Degenerative changes were identified in 21/40 patients (52.5%), 13 (62%) of whom also had BME in vertebral bodies. No differences were found between patients with versus without cervical BME for clinical assessments: numeric rating scale pain (median ± interquartile range) 5.5 ± 3.0 vs 6.0 ± 4.0 (p = 0.69), Funktionsfragebogen Hannover 68.2 ± 41.0 vs 42.0 ± 55.5 (p = 0.19), Northwick pain score 44.4 ± 21.8 vs 47.2 ± 27.0 (p = 0.83), or CRP 0.40 ± 0.80 vs 0.60 ± 0.66 (p = 0.94). For patients with degenerative changes, symptom duration was longer than for patients without (10 ± 12.5 vs 5.0 ± 18.0 yrs, p = 0.73). Conclusion. In this small study of patients with RA and AS complaining about neck pain, BME was found in many different cervical sites, including the facet joints and the spinous processes. However, the occurrence and severity of BME did not correlate with the severity of neck pain.

Comparison of the efficacy and safety of two starting dosages of prednisolone in early active rheumatoid arthritis (CORRA): study protocol for a randomized controlled trial

BackgroundAlthough glucocorticoids are widely used in the treatment of patients with early rheumatoid arthritis, the best dosage of glucocorticoids with regards to efficacy and safety is not known.The aim of the study ‘Comparison of the efficacy and safety of two starting dosages of prednisolone in early active rheumatoid arthritis’ (CORRA) is to compare two standard glucocorticoid starting dosages and the non-use of glucocorticoids in the treatment of patients with early active rheumatoid arthritis on the background of the established ‘anchor’ therapy with methotrexate.Methods/designCORRA is an investigator-initiated, randomized, multicenter, double-blind, placebo-controlled trial with two treatment arms, starting with 60 mg or 10 mg prednisolone per day, tapered down to 5 mg prednisolone within eight weeks, and one placebo arm, each arm comprising 150 patients. The duration of the intervention is 12 weeks. In parallel, all patients will be treated with methotrexate (usual dosage 15 mg/week). The primary efficacy endpoint is the progression of radiographic joint damage after one year compared to baseline. Important secondary endpoints are the percentage of patients in remission, patient global assessment of disease activity, and changes of functional capacity. Safety monitoring is performed.The statistical analysis is performed in three hierarchical steps. The first step is an analysis of covariance (α = 0.05) to compare the group with the initial prednisolone dosage of 60 mg and the placebo group. In case of a statistically significant result, the comparison of the group starting with 10 mg prednisolone with the placebo group will be performed as a second step (α = 0.05). In case of superiority of the 10 mg prednisolone group versus the placebo group, the third step will be a non-inferiority test for the 10 mg prednisolone group versus the 60 mg prednisolone group (α = 0.025).DiscussionThe CORRA trial will yield information concerning the optimal glucocorticoid dosage schedule in the treatment of patients with early rheumatoid arthritis.Trial registrationThis trial was registered on 19 November 2013 at ClinicalTrials.gov. Registration number: NCT02000336.

Interactions between C-reactive protein and traditional risk factors in predicting mortality of older adults

BACKGROUND Elevated levels of C-reactive protein (CRP) are known to be associated with cardiovascular (CV) morbidity and mortality in older adults, however, there seems to be heterogeneity of this association across subsets of individuals. We aim to assess the effects of interactions between CRP and one of the following traditional CV risk factors regarding all-cause mortality in unselected elderly men and women: age, sex, body mass index, diabetes, and hypertension. PATIENTS AND METHODS Three hundred and forty-four general practitioners all over Germany enrolled 6,817 unselected participants, aged 65 years or older, and performed thorough examinations, including CRP measurement at baseline (getABI study). All-cause mortality was determined in the following seven years. Cox regression analyses were done using uni- and multivariable models. RESULTS At baseline 4,172 participants of this cohort had a CRP value of ≤ 3 mg/L (low level CRP group), 2,645 participants had a CRP value of > 3 mg/L (high level CRP group). The unadjusted hazard ratio for all-cause death of the high level CRP group compared to the low level CRP group was 1.49 (95 % confidence interval [95 %CI] 1.34 to 1.66). After adjustment for sex, age, education, peripheral artery disease/media sclerosis, other prior vascular events, smoking status, diabetes, systolic blood pressure, antihypertensive medication, body mass index, cholesterol, and statin use, the hazard ratio was 1.34 (95 %CI 1.20 to 1.50). Significant interactions with CRP were found for sex (adjusted hazard ratio 1.38, 95 %CI 1.11 to 1.72), age (0.75, 95 %CI 0.60 to 0.94), and baseline systolic blood pressure (0.64, 95 % CI 0.51 to 0.81). The interactions of CRP with body mass index and of CRP with diabetes were not significant. CONCLUSIONS In older German adults, there seem to be effect modifications by age, sex, and arterial hypertension regarding the effect of CRP in the prediction of all-cause mortality.

Chronic but not inflammatory changes at the Achilles’ tendon differentiate patients with peripheral spondyloarthritis from other diagnoses – Results from a prospective clinical trial

Background Imaging has an essential role in the new spondyloarthritis (SpA) classification criteria for axial but not for peripheral manifestations. We evaluated the impact of imaging findings for identification and treatment decisions in patients with peripheral spondyloarthritis (pSpA) and controls (non-SpA). Methods Patients with pSpA (Assessment of SpA international Society criteria, n=30) and non-SpA (n=30), aged <45 years, with painful heels or knees, were recruited. Conventional radiography, grey-scale ultrasound including power Doppler (US/PDUS) and MRI of symptomatic areas were performed to assess inflammatory and structural changes. Mann-Whitney U test was used for group comparisons. Results In total, 105 painful entheses (71 heels, 34 knees) in 60 patients were examined. Differences between diagnoses were found for symptom duration (pSpA: 17.2±27.5 vs non-SpA: 4.4±4.3 months), human leucocyte antigen B27 prevalence (67% vs 13%) and gender distribution (53.3% vs 20% male, respectively), all P<0.05. Logistic regression analysis for baseline differences showed that chronic changes (erosions and calcification) in the heel were more frequent in pSpA versus non-SpA by US/PDUS (62.5% vs 28.6% patients and 59.5% vs 26.5% entheses, P<0.05). Inflammatory changes in heel or knee by US/PDUS and MRI could not differentiate between non-SpA and pSpA. Conclusions Differentiation between pSpA and non-SpA was only possible based on structural but not inflammatory changes in the heels and knees of symptomatic patients. US/PDUS was superior to MRI for this purpose. These findings imply that pSpA is associated with erosive changes at enthesitic sites, while inflammation and susceptibility are of minor influence for the development of erosions and calcification to pSpA.

AB0450 Outpatients' Biologic Agent Therapy in Private Practices in Western Germany – a Survey and a Retrospective Study

Background The use of biologic agents has changed treatment paradigms of rheumatic diseases in the past decade. However, the optimal strategy and dosing with this therapy is still not really clear. For example, many biologic agents have not adapted the dosage to the body weight of patients. Furthermore, it is well known that patients in clinical trials and in daily practice may differ substantially. Finally, medication costs is quite an issue in this part of Germany. Objectives To provide real life data including costs of treatment with biologic agents in rheumatology private practices in Westfalia. Methods A total of 13 rheumatologists in Westfalia participated in this retrospective study in 2012 and 2013. Thus, anonymized pooled data of 10.704 patients were analysed with focus on the expenses for medication in general and for biologics. In a second approach Data were extracted from a software tool (RheumaDok). Thus, the annual number of patients treated for inflammatory rheumatic diseases, their diagnosis and biologic agent therapy could be determined. Complete data of 8345 patients could be analysed. Costs were calculated from standard dosing based on the summary of product characteristics (SPC). Results In total, 3083 patients (36.94%) with sero+ and 1958 (23.46%) with sero- rheumatoid arthritis (RA), together 5041 patients (60.41%) with RA were identified, while 778 patients (9.32%) had psoriatic arthritis (PsA) and 956 (11.46%) axial spondyloarthritis (axSpA). Another 1570 (18.81%) had other rheumatic diseases and were excluded from the study. The biologic agent ratio was 7.9% (range 5.5 to 8.7%). Disease specific ratios on RA, PsoA and axSpA are shown in Fig.1. with axSpA as the largest fraction. The overall budget of 11 rheumatologists was 14.3 Mio € per year for all drugs. Of these, 10.47 Mio € (74.37%) were spent for 733 patients (6.85%) on biologics. This reveals annual costs of 14.286 € per patient on biologics, a rate of 65-68% compared to that expected for Etanercept (ETA) or Adalimunab (ADA) by their SPC. Out of allbiological agents employed, the proportion of ETA was 35.1%, of ADA 29.4%, Infliximab 12.3% and others 23.2%. Conclusions The fact that the largest proportion of patients treated with biologics had a diagnosis of axSpA is surprising and deserves further study. The most likely explanation is that rheumatologists take care much more frequently for mild to moderate RA than for axSpA patients. ETA and ADA are the most sold biologics in Germany, this was confirmed for Westfalia. Compared to the official price lists, biologic agents were on average prescribed in a reduced schedule of about 2/3 of the standard dosing. In 2013, the ratio of RA patients on biologic agents was only 6.7%. This is a considerably low figure compared to data of the German core set documentation (25%)1. References S. Bischoff et al. (2012) Kerndokumentation, http://dgrh.de/fileadmin/media/Forschung/Versorgungsforschung/ErwachsenenKerndok/standardpraesentation_2012_dgrh_extern.pdf Acknowledgements Partially sponsored by an unrestricted grant by Pfizer Disclosure of Interest None declared