Elena Frati

Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: Comparison of adalimumab, etanercept and infliximab in the GISEA registry

OBJECTIVE To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.

Extracorporeal shock wave therapy for chronic calcific tendinitis of the shoulder: single blind study

Objective: To evaluate the clinical and radiological response of chronic calcific tendinitis of the shoulder to extracorporeal shock wave therapy (ESWT) in a single blind study. Methods: 70 patients showing chronic, symptomatic, calcifying tendinitis of the shoulder were examined. A single blind randomised study was performed with 35 patients undergoing a regular treatment (group 1) and 35 a simulated one (group 2). Pain and functional assessment was carried out according to Constant and Murley. Variations in the dimension of the calcification were evaluated by anteroposterior x ray films. Results: A significant decrease of pain and a significant increase in shoulder function was seen in group 1. Examination by x ray showed partial resorption of the calcium deposits in 40% of cases and complete resorption in 31% of cases in group 1. In the control group no significant decrease of pain and no significant increase in shoulder function was seen. No modifications were observed by x ray examination. Conclusion: Because of its good tolerance, safety, and clinical radiological response, ESWT can be considered as an alternative treatment for chronic calcific tendinitis of the shoulder.

Efficacy of extracorporeal shock wave treatment in calcaneal enthesophytosis

OBJECTIVE To evaluate the efficacy of extracorporeal shock wave treatment (ESWT) in calcaneal enthesophytosis. METHODS 60 patients (43 women, 17 men) were examined who had talalgia associated with heel spur. A single blind randomised study was performed in which 30 patients underwent a regular treatment (group 1) and 30 a simulated one (shocks of 0 mJ/mm2 energy were applied) (group 2). Variations in symptoms were evaluated by visual analogue scale (VAS). Variations in the dimension of enthesophytosis were evaluated byx ray examination. Variations in the grade of enthesitis were evaluated by sonography. RESULTS A significant decrease of VAS was seen in group 1. Examination byx ray showed morphological modifications (reduction of the larger diameter >1 mm) of the enthesophytosis in nine (30%) patients. Sonography did not show significant changes in the grade of enthesitis just after the end of the treatment, but a significant reduction was seen after one month. In the control group no significant decrease of VAS was seen. No modification was observed byx ray examination or sonography. CONCLUSION ESWT is safe and improves the symptoms of most patients with a painful heel, it can also structurally modify enthesophytosis, and reduce inflammatory oedema.

No association between human parvovirus B19 infection and Sjögren’s syndrome

The association of human parvovirus B19 (HPVB19) infection with autoimmune disease, including systemic lupus erythematosus, rheumatoid arthritis, polymyositis, and vasculitis, has been suggested, although the exact relationship between the infection and these disorders has not been fully elucidated.1,2 A recent report showed serological evidence of past B19 infection associated with the presence of cytopenia in patients with primary Sjogren’s syndrome (SS).3 To gain more information about the aetiopathogenetic role of HPVB19 for this disease, we evaluated the presence of the viral genome in minor salivary glands from patients with primary SS. We studied 10 women with SS (mean (SD) age 45 (9) years) and 10 healthy controls matched for age (43 (6) years) and sex. SS was diagnosed according to European criteria.4 Each subject taking part in the study underwent minor …

Diff Quik staining method for detection and identification of monosodium urate and calcium pyrophosphate crystals in synovial fluids

OBJECTIVE To evaluate whether the Diff Quik (DQ) staining method might prove useful in identifying monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals on permanent mounted stained slides. METHODS 27 synovial fluid (SF) samples obtained from the knees of 21 patients with acute CPPD disease and 6 with acute gout were studied. Wet analysis for crystal detection and identification was performed within one hour of joint aspiration. In addition, 16 inflammatory synovial effusions obtained from patients with knee arthritis induced by non-crystalline inflammatory diseases were studied. For each SF, a DQ stained slide was analysed by two of the authors trained in SF analysis. The observers were blinded to the type of crystals present in the SF. Each slide was analysed by compensated polarised as well as transmitted light microscopy. An SF was considered positive if intracellular and/or extracellular crystals were clearly identified. In addition, the observer was asked to identify the type of the crystals using compensated polarised light microscopy. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of the DQ staining method were determined. RESULTS 51 true positive and 28 true negative cases were correctly classified (39 CPPD samples, 12 MSU samples, 28 samples of crystal unrelated arthropathies). Overall, four false positive and three false negative cases were reported. In all the false positive cases, extracellular CPPD crystals were erroneously identified, whereas CPPD crystals present in the SF were not identified in the three false negative cases. All MSU specimens were correctly diagnosed. The overall specificity, sensitivity, and accuracy using DQ stained slides for crystal confirmation were respectively 87.5%, 94.4%, and 91.9%. The PPV was 92.7% and the NPV 90.3%. In particular, the specificity, sensitivity, and accuracy for CPPD detection were 90.9%, 92.9%, and 91.9%, with a PPV of 90.7 and an NPV of 93.0%. All the MSU specimens were correctly identified, providing 100% sensitivity, specificity, accuracy, PPV, and NPV. CONCLUSIONS Stained preparations of SF, including DQ stained smears, could provide a useful tool for delayed SF analysis suitable for quality controls, including cytological examination and crystals detection and identification.

Switch from infliximab to infliximab biosimilar: efficacy and safety in a cohort of patients with different rheumatic diseases

Dear Editor in Chief We read with great interest the manuscript by Nikiphorou et al. describing the effectiveness of infliximab-biosimilar CTP13 (INB) used as a switch from Remicade® (Janssen Biotech, Inc., Horsham, PA, USA) (infliximab (INX)) in patients with different established rheumatic diseases [1]. Thirty-nine patients on INX were switched to biosimilar after a mean time (SD) of 4.1 (2.3) years. The authors reported that INB clinical effectiveness, during the first year of switching, was comparable to INX in both the patient-reported outcomes and disease-activity measures, with no immediate safety signals. Eleven patients (28.2%) discontinued INB due to INX antibodies detected prior to INB infusion (3/11), latent tuberculosis (1/11), new-onset neurofibromatosis (1/11), and subjective reasons with no objective deterioration of disease (6/ 11). The authors suggested that subjective reasons, such as negative expectations, played a key role among INB discontinuations. In this regard, we report herein our experience in a cohort of 23 patients followed in our unit for different rheumatic diseases and switched, for local regulatory issues, to INB (Inflectra®) after amean time (SD) of 71.65 (44.40) months on INX (Remicade). More in detail, 11 out of 23 had psoriatic arthritis (7 with peripheral and 4 with axial involvement), 8/23 ankylosing spondylitis, 2/23 rheumatoid arthritis, 2/23 Crohn’s disease and associated axial spondyloarthritis, and 1/23 Behçet’s disease and associated axial spondyloarthritis. At the time of the switch, all of the patients were in complete disease remission on INX at a dose of 5 mg/kg every 8 weeks. After a mean time of 1.71 months (range 1–2) from the start of INB a disease relapse occurred in 7 out of 23 patients (30.43%). Their mean (SD) duration of previous INX treatment was 62.28 (49.95) months. Table 1 summarizes the clinical, demographic, and therapeutic data of the 7 subjects unresponsive to INB. INB was then suspended and IFX was readministered in all 7 patients at a dose of 5 mg/kg every 8 weeks, in association with a tapering dose of oral corticosteroids. In 5/7, the readministration of INX promptly led to a remarkable clinical improvement (4/5), or at least a partial one (1/5), with a significant decrement of the disease activity indexes. No amelioration was observed in 2/7 subjects. Among the 16 patients that were still on treatment with INB, 7 of them were under close observation and monitoring for uveitis relapse (1/7), recurrence of psoriatic lesions (1/7), arthralgia (4/7), and referredworsening of global quality of life (1/7). No changes in the response to treatment were observed in 9 out of 23 subjects (39.13%). INB was well tolerated and no adverse events were noted. In PLANETAS and PLANETRA studies, INB demonstrated equivalent efficacy to INX at 30-week follow-up, with a comparable pharmacokinetic profile and immunogenicity both in patients affected by ankylosing spondylitis (AS) and rheumatoid arthritis (RA) [2,3]. INB efficacy and safety have been confirmed also in the extension of the PLANETAS study in AS at 54-week follow-up [4]. Nevertheless, data on the effectiveness of the switch from INX to INB in patients in a stable disease remissionwhile on IFX are scarce, and future studies are needed. For the above reason, real-life data should be welcome, even though from uncontrolled series, until further trials are performed. In our cohort of patients, 30% of subjects switched from IFX to INB while in disease remission showed a rapid worsening of disease activity indexes. Moreover, 30% of patients still on treatment with INB were under evaluation for the potential reduction of the interval between INB administrations either the potential increase of INB dosage or a further switch from INB to IFX, due to a suspected lack of efficacy. Overall, it is unlikely that in our cohort of patients, only subjective reasons have played a role in the poor outcome observed in most subjects. Indeed, we did not observe any change in the response to treatment in only 40% of cases. Limitations of our study were the small number of patients, the absence of a control group, and the short-

CD36 and CD14 immunoreactivity of Reiter cells in inflammatory synovial fluids

Reiter cells are macrophages containing ingested polymorph nuclei that are commonly found in most inflammatory synovial fluids. Available data indicate that CD36 and CD14 on human monocyte derived macrophages are adhesion molecules involved in several biological processes.1 Of interest, their role in the process of adhesion and phagocytosis of apoptotic cells has been recently demonstrated.2-5 Jones and colleagues demonstrated reduced Reiter cells in the synovial fluids from patients with rheumatoid arthritis. This observation is consistent with the hypothesis that Reiter cells play a regulatory part in preventing autolysis of polymorphonuclear neutrophils (PMN) and thus local tissue damage.6 The purpose of this study was to evaluate by histochemical technique whether Reiter cells express CD36 and CD14 in inflammatory synovial fluids. We analysed the synovial fluids obtained from the knee joints of 10 patients suffering from inflammatory joint diseases of recent onset (< 6 weeks). Three patients had seropositive active rheumatoid arthritis, four patients had seronegative spondyloarthritis (two reactive arthritis, one psoriatic arthritis, one enteroarthritis) and three patients had …

Rotator cuff tear associated with an acromioclavicular cyst in rheumatoid arthritis

We report two cases of a full-thickness rotator cuff tear followed by acromioclavicular cyst formation in patients with longstanding erosive polyarticular rheumatoid arthritis. One of the consequences of a ratator cuff tear is articular instability with upward migration of the humeral head. The ensuing chronic friction against the undersurface of the acromio-clavicular joint caused by arm movements can lead to a non-inflammatory effusion of the acromioclavicular joint with cyst formation. Clinical and ultrasonographic features and a pathogenetic hypothesis are discussed.

THU0163 Low Doses of Etanercept Can be Effective to Maintain Remission in Psoriatic Arthritis Patients

Background Etanercept (ETN) has been proven to be highly effective in the treatment of patients with Psoriasic Arthritis (PsA) that continued to be active despite treatment with DMARDDs and NSAIDs. In PsA patients achieving a prolonged remission with ETN 25 mg biweekly may be done a switch to ETN 50 mg weekly, while it can not be done a weekly regimen without increased dose. However emerging data from the common clinical practice, and the results of the few observational studies in literature suggest the possibility of identifying the lowest effective dose of ETN for a considerable percentage of PsA patients. Objectives We wanted to do a prospective open-label study to evaluate if PsA patients in clinical remission with biweekly ETN 25 mg therapy could be switched to weekly regimen or even to every other week regimen without increased dose for injection. Methods 56 PsA patients, classified according to the CASPAR criteria (26 patients (46%) with peripheral poliarthritis, 12 patients (24%) with axial pattern and 16 patients (28%) with peripheral oligoarthritis) were recruited between January 2009 and December 2012 at the Rheumatology Unit of Azienda Ospedaliera Universitaria Senese. Patients had to have a disease duration of >1 year and be age >18 <65 years and had active disease, defined as ≥3 tender joints and ≥3 swollen joints) for the patients with peripheral arthritis and as a BASDAI >4 for the patients with axial involvment, despite conventional treatment. Included patients self-administered 25 mg of ETN (Wyett) subcutaneously. Patients were followed up during 1 year and evaluated at baseline and every 3 months thereafter: at each visit all patients underwent routine joint, general assessment and serum and urine samples: measures of effectiveness included PASI, DAS 28, BASDAI and achievement of clincal remission (value of <2 on a 1-10 point scale in each of four ASAS domain, score BASDAI <2, absence of peripheral arthritis e/o enthesitis, absence of inflammatory extra-articular manifestations, normalization of acute phase reactants (CRP), without taking any additional drug including NSAIDs and CS) According to the protocol, patients, who were in clinical remission with biweekly ETN 25 mg at week 12° and 16°, were switched to an weekly regimen without a change of the dose. If clinical remission, despite the reduction of the dose, persists at week 24° and 28°, patients were switched to an every-other-week regimen, continuing with this administration schedule for the entire duration of the study if at week 36° and week 46° clinical remission was maintained. Results At the end of the study 31 patients (55%) were still in remission, 6 (11%) with a weekly regimen and 20 (37%) with a every-other-weekly regimen. Conclusions Our study indicates that a consistent percentage of subjects with PsA, treated with ETN 25 mg biweekly, achieved clinical remission within the first three months of therapy and also that a substantial percentage of these patients mantains the partial remission with an every-other-week regimen. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4196

THU0281 Efficacy of etanercept therapy with an every other week regimen in patients with ankylosing spondylitis

Background Efficacy and safety of etanercept 25 mg twice weekly was comparable to 50 mg once weekly in adult patients with ankylosing spondylitis (AS). We know that AS patient who were treated initially with Etanercept 25 mg twice weekly could be switched to once weekly but with increased dose per injection at 50 mg. Howeverrecent evidences suggest that etanercept 25 mg once weekly is effective enough to maintain remission for AS among korean patients. In addition discontinuation of etanercept 25 mg usually results in the relapse of disease activity but only after some weeks inAS patients in remission. Objectives To evaluate if patients with AS in remission with biweekly etanercept therapy could be switched to an every-other-week regimen,without increased dose per injection. Methods 38 patients with AS diagnosed at least from 1 year were enrolled, according to the modified 1984 New York Criteria for ASwith by minor to moderate radiographic evidence of spinal structural damage (Stage I-III). All patients had active AS (BASDAI>or=4), despite treatment with NSAIDs. Exclusion criteria included the presence of significant comorbidities, including active infection, cardiac insufficiency (NYHA class III/IV),malignancy, elevated liver enzymes, creatinine serum level >1,20 mg/l, alcohol and/or drug abuse, pregnancy, demyelinating diseases. Before being recruited for the study, patients were screenedfor latent tuberculosisandfor viral hepatitis. Patients meeting the inclusion and exclusion criteria self-administered 25 mg of etanercept (Wyett) subcutaneously twice weekly for sixteen weeks.According to the protocol,patient withclinical remission (defined as ASAS criteria and BASDAI<2) were switched to an weekly etanercept regimen without a change in dose at weeks 12 and 16 and to an every-other-week regimen at week 24. A follow-up was performed at week 36 and 48 to evaluate clinical efficacy.In case of a relapse of the disease activity etanercept 25 mg twice a week were administered again. Results All patients received for 16 weeks a dose of 25 mg twice a week.The percentage of ASAS 20 responders was 81% (31 patients). Among them, 18 (47,3%)with persistent remission (week 12 and 16) were switched to an weekly regimen without a change in dose, while the other 13continued with biweekly etanercept therapy. At week 24, 15 patients (85%) were stable and among them 14 patients (93%) had clinical efficacy at week 36 and 54. At week 24, 3 patients (15%) did not show beneficial effects and they continued with etanercept 25 mg twice a week. There were no statistically significant differences in the incidence of adverse events between the biweekly etanercept therapy group (16 pt) and the every-other-week etanercept therapy group (14 pt). Baseline characteristics associated with a major clinical response to etanercept were a shorter disease duration, younger age, raised CRP and a higher BASDAI. Conclusions Our study indicatesthat a consistent percentage of subjectswith AS (37%), differently from RA, treated with etanercept,maintains the remission also with an every-other-week regimen. Thisfinding may suggest that the AS patients in clinical remission with biweekly etanercept could be switched to an every-other-week regimen, without increased dose per injection, with relevant lowering of economic andsafety burden. Disclosure of Interest None Declared