Real-world effectiveness of abatacept for rheumatoid arthritis treatment in European and Canadian populations: a 6-month interim analysis of the 2-year, observational, prospective ACTION study.

BACKGROUND: Discontinuation of rheumatoid arthritis (RA) treatment for lack or loss of initial response, tolerability issues, or development of antibodies against the therapeutic agent remains a challenge in clinical practice. Here we present a 6-month interim analysis of a 2-year prospective observational trial in Europe and Canada aiming to assess the real-world effectiveness, safety, and tolerability of intravenous abatacept for the treatment of moderate-to-severe RA. METHODS: ACTION (AbataCepT In rOutiNe clinical practice) is a prospective, observational study assessing effectiveness, safety, and tolerability of abatacept in patients with RA enrolled in Europe and Canada between May 2008 and January 2011. The patient population was divided into two groups: biologic naïve ('first-line') patients and patients who had previously failed treatment with at least one biologic agent ('second-line'). Retention rates were calculated using Kaplan-Meier curve estimates. Effectiveness was measured using European League Against Rheumatism (EULAR) response criteria, the 28-item Disease Activity Score, the Clinical Disease Activity Index (CDAI), and physical function, as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Serious adverse events (SAEs) were reported for all enrolled patients. RESULTS: Of 1138 consecutively enrolled patients, 1114 and 1079 patients were evaluable for retention and effectiveness, respectively. Overall, retention rates were 88.6% (95% confidence interval [CI]: 86.4, 90.4); 67.4% of patients achieved good/moderate EULAR response; 32.8% had a CDAI Low Disease Activity State (LDAS); and 44.7% a HAQ-DI response. Retention rates among first- and second-line patients were 93.0% (95% CI: 85.9, 96.6) and 88.1% (95% CI: 85.7, 90.0), respectively. The percentage of patients achieving CDAI LDAS was 40.0% (95% CI: 26.4, 53.6) for first- and 32.2% (95% CI: 28.4, 36.0) for second-line patients and the proportion achieving a HAQ-DI response was 60.3% (95% CI: 47.8, 72.9) versus 43.1% (95% CI: 39.0, 47.2), respectively. The incidence of SAEs was 4.7%. CONCLUSIONS: Evidence from this 6-month interim analysis suggests that abatacept offers an effective and well-tolerated treatment option for patients with RA, including those who have previously failed anti-tumor necrosis factor treatment. In addition, higher retention rates and effectiveness outcomes were observed when abatacept treatment was initiated earlier in the course of the disease.

The detection of calcium pyrophosphate crystals in the synovial fluid of patients with rheumatoid arthritis using the cytospin technique: prevalence and clinical correlation.

There are only a few studies dealing with the detection and clinical impact of calcium pyrophosphate (CPPD) crystals in patients with rheumatoid arthritis (RA) published to date. In particular, data determined by the cytospin technique, which is an effective tool to enhance the crystal detection rate, are lacking. The objectives of this study were to determine the prevalence of CPPD crystals in the synovial fluid (SF) of patients with RA and to investigate whether the detection of CPPD crystals is correlated with demographic, clinical and serological features. We examined 113 consecutive SF samples of patients with RA, obtained from therapeutic arthrocentesis of knee joints. After cytocentrifugation, the sediments were examined by polarized microscopy for the occurrence of CPPD crystals. Demographic, clinical and serological data, acquired from the medical records, were compared between crystal-positive and crystal-negative subjects. CPPD crystals were observed in 20 of the 113 cases, representing 17.7%. CPPD-positive and CPPD-negative subjects did not differ significantly in sex, duration of disease, Steinbrocker radiologic stage, disease activity score 28, as well as serum rheumatoid factor and anti-CCP positivity. Patients positively tested for CPPD crystals had a significantly higher age than CPPD-negative patients (p < 0.0001). An age-independent association of long-time treatment with diuretics and CPPD crystal formation was not found. In conclusion, demographic, clinical and serological characteristics of patients with RA were not associated with the occurrence of CPPD crystals. Age was the only significant influencing factor on CPPD crystal formation in patients with RA.

The cytospin technique improves the detection of calcium pyrophosphate crystals in synovial fluid samples with a low leukocyte count.

In synovial fluids (SF) with low leukocyte or/and crystal counts, important features may be missed, if exclusively smears are examined by polarized microscopy. That may be overcome by cytocentrifuges, which use low-speed centrifugal force to concentrate cells onto a glass slide and thus enhance the number of cells per high power field (HPF). We compared the calcium pyrophosphate (CPP) crystal counts in cytospin preparations with those in common smears of SF. The number of CPP crystals was counted in 50 SF samples by polarized microscopy, and statistical comparisons of the mean values of the cytospin and smear preparations were performed using the Wilcoxon test. The reproducibility within the slides of the cytocentrifuge and smear samples was determined by Spearman's rank correlation. The crystal counts were significantly higher in the cytospin than in the smear preparations (median 96/10 HPF vs. 2.5/10 HPF, p < 0.0001). The correlation in the crystal count between the slides 1 and 2 was significantly higher within the cytocentrifuge than in the smear group (0.97 vs. 0.73, p = 0.0004). CPP-negative cytospin preparations in initially smear-positive slides were not observed. We confirmed that the cytospin technique significantly enhances the number of examinable crystals per HPF, compared to common smears.

Familial Mediterranean fever without fever as a cause of monoarthritis.

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease. FMF-related arthritis affects large joints, especially in the lower extremities. It starts with acute pain and swelling and affects one joint at a time. Fever is the most common symptom in FMF. Monoarthritis as the sole symptom is relatively rare and thus delayed diagnosis of the disease in a patient who had been suffering from monoarthritis for several years. Genetic analysis showing typical mutations in the patient eventually resulted in correct diagnosis, although classical clinical diagnostic criteria were not met. The patient received appropriate therapy with colchicine, which led to remission of the symptoms.

Occurrence of relapsing polychondritis with a rising cANCA titre in a cANCA-positive systemic and cerebral vasculitis patient.

Relapsing polychondritis (RP) is a relatively rare disorder, with a high death rate that affects cartilaginous structures. RP can be either primary or secondary as part of autoimmune syndromes. We present a case of RP in a 49-year-old man suffering from cytoplasmic antineurophil cytoplasmic antibodies (cANCA) positive vasculitis, admitted to our hospital with red swollen left ear and painful sternoclavicular joint and larynx. The patient was in remission from the vasculitis but manifested a high cANCA titre indicating vasculitis activity. With his high cANCA titre vasculitis, full manifestation of RP concomitantly occurred. After a successful cortisone treatment for RP, the patient received cyclophosphamide treatment for his vasculitis that resulted in a decrease in cANCA titre and full remission of his RP symptoms.

The detection of calcium pyrophosphate crystals in sequential synovial fluid examinations of patients with osteoarthritis: once positive, always positive.

The aim of this study was to investigate whether calcium pyrophosphate dihydrate (CPPD) crystals are constantly detectable in sequential synovial fluid (SF) examinations of patients with initially CPPD-positive osteoarthritis (OA). For this purpose, we searched our SF database for CPPD-positive patients, who had two or more SF analyses between 2008 and 2012 to get sequential information. The database contains SF data determined by a standardised procedure. Of 1,878 samples, examined within the defined time period, 60 samples from sequential SF analyses of 23 patients were eligible for this study. The number of examinations ranged from 2 to 7 (median, 2), and the median interval between the first and last arthrocentesis was 12 months (2-43). CPPD crystals were detected in all of the sequentially examined samples according to the defined criterion of positivity. All of the subjects had OA of the knee, with a median Kellgren-Lawrence grade of 3 in the initially performed X-rays, and meniscal calcifications were found in six subjects. In conclusion, our results suggest that CPPD crystals are a regular feature of sequentially examined SF of initially CPPD-positive patients with symptomatic OA of the knee.

B lymphocyte-typing for prediction of clinical response to rituximab.

INTRODUCTION: The prediction of therapeutic response to rituximab in rheumatoid arthritis is desirable. We evaluated whether analysis of B lymphocyte subsets by flow cytometry would be useful to identify non-responders to rituximab ahead of time. METHODS: Fifty-two patients with active rheumatoid arthritis despite therapy with TNF-inhibitors were included in the national rituximab registry. DAS28 was determined before and 24 weeks after rituximab application. B cell subsets were analyzed by high-sensitive flow cytometry before and 2 weeks after rituximab administration. Complete depletion of B cells was defined as CD19-values below 0.0001 x109 cells/liter. RESULTS: At 6 months 19 patients had a good (37%), 23 a moderate (44%) and 10 (19%) had no EULAR-response. The extent of B lymphocyte depletion in peripheral blood did not predict the success of rituximab therapy. Incomplete depletion was found at almost the same frequency in EULAR responders and non-responders. In comparison to healthy controls, non-responders had elevated baseline CD95⁺ pre-switch B cells, whereas responders had a lower frequency of plasmablasts. CONCLUSIONS: The baseline enumeration of B lymphocyte subsets is still of limited clinical value for the prediction of response to anti-CD20 therapy. However, differences at the level of CD95⁺ pre switch B cells or plasmablasts were noticed with regard to treatment response. The criterion of complete depletion of peripheral B cells after rituximab administration did not predict the success of this therapy in rheumatoid arthritis.

Dried cytospin preparations of synovial fluid are a stable material for long-time storage and delayed crystal analysis.

The aim of this study was to evaluate dried SF cytospin preparations as a suitable medium for long-time storage and delayed crystal analysis. For this purpose, we analyzed ten MSU-positive, ten CPPD-positive and 20 crystal-negative SF at baseline (wet preparation), after 24 h, 1 week, 4 weeks, 6 months and 12 months for the occurrence of crystals. After cytocentrifugation for 10 min at 700 rpm in a Shandon Cytospin 4 cytocentrifuge (Thermo Fisher Scientific, Waltham, USA), the sediments were dried on the slides and examined in blinded fashion at any time point by an experienced analyst using polarized microscopy. The crystal content of the initially MSU- and CPPD-positive samples was positively confirmed at any time point of the study, whereas the controls remained crystal-negative during the whole study period. Thus, compared to the examined wet preparations at baseline, there were no false positive or false negative results observed. In conclusion, dried cytospin preparations were confirmed as a suitable material for long-time storage and delayed crystal identification.

Pseudoeosinophilia of synovial fluid is caused by crystals mimicking the distinct light scattering fractions of eosinophilic granules.

BACKGROUND: Automated leukocyte differential counts of synovial fluid (SF) can be influenced by laboratory artefacts. Pseudoeosinophilia of SF has recently been first described in association with monosodium urate and calcium pyrophosphate crystals. This study compared automated measurements of the percentages of SF leukocyte fractions by two haematology analysers in order to elucidate the underlying mechanism of pseudoeosinophilia. METHODS: The percentages of the leukocyte fractions of 17 crystal-containing and 28 crystal-free specimens were compared using the Wilcoxon test. Measurements were performed using the Cell-Dyn 3200 and the ADVIA 2120i, which are based on different techniques. RESULTS: The percentages of eosinophils of the crystal-positive samples determined by the Cell-Dyn 3200 were significantly higher than those assessed by the ADVIA (p<0.0001), whereas the percentages of eosinophils of the controls did not differ significantly between the two devices (p=0.95). The Cell-Dyn 3200 clearly showed the phenomenon of crystal-associated pseudoeosinophilia (p<0.0001), which did not occur in the ADVIA measurements (p=0.28). The percentage of neutrophils was to a lower degree elevated in the crystal group (p=0.015). CONCLUSIONS: It was confirmed that SF crystals interfere with the typical light scattering fractions of leukocyte granules and may thus lead to spuriously elevated percentages of eosinophils and neutrophils in SF specimens.

[Prophylaxis and therapy of the glucocorticoid-induced osteoporosis - a review of recent guidelines]. / Prophylaxe und Therapie der Glukokortikoid-induzierten Osteoporose - rezente Leitlinien im Überblick.

Several international guidelines for treatment and prophylaxis of glucocorticoid-induced osteoporosis (GIO) have been published. Consistent with the development of new therapeutic agents, a different approach to treatment can be recognized depending on the year of publication. Also, new insights for the postmenopausal osteoporosis leave their marks on recent guidelines. The working committee on Osteology of the Austrian Society for Rheumatology and Rehabilitation (ÖGR) sifted through actual guidelines and recent literature on the topic to develop recommendations for the prophylaxis and treatment of the GIO.

Calcium pyrophosphate and monosodium urate crystals in synovial fluid as a cause of pseudoeosinophilia.

BACKGROUND: Synovial fluid (SF) leukocytes can be counted microscopically in a Neubauer chamber or by automated procedures using haematology analysers. Knowledge of laboratory artefacts is crucial for the correct interpretation of results obtained using automated methods. SF pseudoeosinophilia has recently been described as a new artefact in patients with crystal-related arthropathies. We investigated whether pseudoeosinophilia of SF is restricted to crystal-related disorders, or if it may also occur in other arthropathies. METHODS: We compared the percentages of eosinophils in 120 crystal containing SF samples with 185 crystal-free specimens using the Wilcoxon test. Crystal positive samples, determined by polarised microscopy, contained at least two monosodium urate or calcium pyrophosphate crystals per 10 high power fields (630× magnification). True SF eosinophilia was ruled out by microscopic examination of stained slides. RESULTS: Crystal positive samples had significantly higher percentages of eosinophils than the controls (p<0.0001). No significant differences between the two crystal types were found (p=0.693). Thus, pseudoeosinophilia was significantly correlated with the presence of crystals, and none of the distinct crystal types was more likely to be associated with pseudoeosinophilia. CONCLUSIONS: In this study, SF pseudoeosinophilia was confirmed as a crystal-related laboratory artefact which has to be considered in the interpretation of automated SF leukocyte differential counts.

Evaluation of platelet function and pharmacological platelet inhibition in patients with myeloproliferative disorders using multiple electrode aggregometry.

BACKGROUND: The aim of this study was to describe platelet aggregation characteristics by multiple electrode aggregometry (MEA) and to evaluate MEA for its potential to detect platelet dysfunction and response to anti-aggregatory drugs in patients with myeloproliferative disorders (MPD). METHODS: We compared the platelet response to arachidonic acid (ASPI test), adenosine diphosphate (ADP test) and thrombin receptor activating peptide (TRAP test) in hirudin-anticoagulated blood of 55 patients with polycythaemia vera and essential thrombocythaemia and 75 controls. RESULTS: Comparing MPD patients and controls no statistically significant difference indicative of platelet dysfunction was found in MPD patients. Analysis of covariance revealed platelet- and leukocyte count as a significant influencing factor on MEA function. Furthermore we could demonstrate that ASA and clopidogrel treatment results in a statistically significant lower ASPI (Controls: p<0.0001, MPD: p<0.0001) and ADPtest value (MPD: p=0.00125) compared to untreated patients thereby validating the method for monitoring of anti-aggregatory therapy. CONCLUSION: In this study MEA was confirmed as a valid method for monitoring of ASA and clopidogrel treatment in patients with MPD and normal control subjects. The platelet and leukocyte count were identified as major influencing factors on MEA aggregation tests both in MPD patients and controls. No functional platelet abnormalities were detected in MPD patients.

The use of tumour necrosis factor alpha-blockers in daily routine. An Austrian consensus project.

To define relevant disease parameters and their respective limits indicating the initiation of TNF-alpha-blockers in individual patients. Subsequently, to analyze retrospectively patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), who started TNF-alpha inhibition in 2006. Points to consider, regarded relevant for individual treatment decisions as well as their assessment methods, were ascertained by experts' consensus applying the Delphi technique. Subsequently, these parameters' thresholds with respect to the initiation of a TNF-alpha-blocker were identified. Thereafter, the rheumatologists representing 12 centres all over Austria agreed to retrospectively analyze their patients started on a TNF-alpha-blocker in 2006. Experts' opinion regarding disease parameters relevant to initiate TNF-alpha-blockers in RA patients only slightly differed from those applied in clinical trials, but the parameters' threshold values were considerably lower. For PsA patients, some differences and for AS patients, considerable differences between experts' opinion and clinical studies appeared, which held also true for decisive parameters' means and thresholds. Six hundred and fifty patients, started on TNF-blockers in 2006, could be analyzed retrospectively, 408 RA patients (53.3 years mean, 340 females), 93 PsA patients (48.9 years mean, 59 males) and 149 AS patients AS (42.2 years mean, 108 males), representing approximately 25% of all Austrian patients initiated on a TNF-blocker in this respective year. Far more individualized, patient-oriented treatment approaches, at least in part, are applied in daily routine compared with those derived from clinical trials or recommendations from investigative rheumatologists.