Acute pain: a multifaceted challenge - the role of nimesulide.

BACKGROUND: This article summarizes the outcome from an international consensus meeting, which took place in Vienna on 4 November 2014. SCOPE: The aim of the meeting was to provide the state of the art on the pathophysiology and treatment of acute pain with special emphasis on nimesulide, a non-steroidal anti-inflammatory drug (NSAID) indicated for the treatment of acute pain and primary dysmenorrhea. Besides the data on the mechanisms of acute inflammatory pain and on the efficacy and safety of nimesulide in patients affected by different forms of acute pain, the clinical experience of attending experts was discussed based on selected case reports. RESULTS: The members of this consensus group recognized that nimesulide is a NSAID highly effective in the treatment of several painful situations with an acute inflammatory component including primary dysmenorrhea. Although safety concerns regarding nimesulide have emerged in recent years, both robust new epidemiological data and clinical experience confirm a positive benefit/risk profile of nimesulide in the treatment of several forms of acute pain. CONCLUSIONS: The members of this international consensus group concluded that nimesulide, when used appropriately, remains a particularly valuable and safe option for the treatment of several conditions characterized by the presence of acute inflammatory pain because of the rapid onset of the analgesic action, and the positive evidence-based benefit/risk profile.

Parathyroid cysts, a rare condition: a case report and review of the literature.

Parathyroid cysts are a rare medical condition, that is why they represent a diagnostic and therapeutic challenge for the practitioner. The cysts are often small in diameter, measuring a few millimeters, but in some cases they are centimetric in size. There are 2 types of parathyroid cysts, according to their activity: the nonfunctioning (essential) and the functioning (adenomatous) forms, the last one being responsible of hyperparathyroidism. We report a case of nonfunctioning symptomatic parathyroid cyst in a 36-year old woman revealed by an anterior cervical tumefaction focusing on the pre-operative diagnosis and the management of it regarding the various therapeutic methods described in the literature.

Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial.

UNLABELLED: Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years. INTRODUCTION: We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis. METHODS: In the core study, healthy postmenopausal women with osteoporosis (N=7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere. RESULTS: A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium. CONCLUSION: Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years.

Isolate vertigo crisis revealing an endolymphatic sac tumor.

UNLABELLED: Endolymphatic sac tumors are rare entities that have a destructive potential on the temporal bone. They are aggressive tumors presenting as low-grade papillary adenocarcinoma, but there are no reports of metastasis in the literature. The Von Hippel-Lindau disease is a hereditary condition caused by germinal mutations of the tumor-suppressor VHL-gene. We present the case of an endolymphatic sac tumor associated with the Von Hippel-Lindau disease at a 46-year-old patient revealed by an isolate vertigo crisis, discussing the management of the tumor and the clinical, imaging, genetic and histopathologic features of it. CONCLUSIONS: Endolymphatic sac tumors have recently been described as part of the Von Hippel-Lindau disease, a genetic disorder involving the development of hypervascular tumors. The treatment depends on the size of the tumor, however surgical approach is the most successful choice and can be associated or not with radiotherapy.

Surgical management of the thyroid nodules.

The evaluation and the management of thyroid nodules have evolved during the last years. Before the 1980's the strategy was relatively simple, the palpable thyroid nodules were explored by scintigraphy, a method that separated the "hot" nodules (with a low possibility of being cancer) from the "cold" nodules (that included most types of cancer). During the last 25 years, the development of new techniques such as HRUS( high resolution ultrasonography) and HRUS-guided FNAB (fine-needle aspiration biopsy) slowly replaced the 'traditional' methods. As a consequence, the management of the thyroid nodules has become more and more complex but with greater expenses. The objective of this paper is to evaluate the thyroid nodules and their management. We retrospectively reviewed the medical charts of 40 patients managed at our departments for thyroid nodules over a 5-year period (january 2004-december 2008). The evaluation of every patient included physical examination, serum TSH, T3 and T4 levels in some cases serum calcitonin levels, cervical ultrasonography--HRUS or cervical color Doppler ultrasonography, HRUS-guided FNAB, using surgical specimen histology as the reference. The histological examination of the surgically-removed thyroid nodules found the evidence of malignancy in 7 cases with a rate of cancer of 17.5% in the studied population. Age older than 70 years, a hard nodule upon palpation, hypoechogenicity and micro-calcifications significantly predicted cancer. This study highlights the fact that apart from the histological examination of the surgical specimen, HRUS and HRUS-guided FNAB are the best diagnostic tools for differentiating benign thyroid nodules from suspicious or malignant nodules.

Inhibition of radiographic progression with combination etanercept and methotrexate in patients with moderately active rheumatoid arthritis previously treated with monotherapy.

OBJECTIVE: To determine the effect of changing from etanercept or methotrexate monotherapy to etanercept plus methotrexate combination therapy on radiographic progression in rheumatoid arthritis (RA) patients. METHODS: Patients enrolled in this 1-year open-label study previously completed a 3-year blinded study in which they received methotrexate or etanercept monotherapy or the combination of both. All patients received the combination of etanercept 25 mg subcutaneously twice weekly plus oral methotrexate up to 20 mg/week. The primary radiographic endpoint was a change in modified total Sharp score (TSS), as assessed by blinded readers. RESULTS: At baseline, patients previously receiving methotrexate monotherapy (etanercept-added, n = 52) or etanercept monotherapy (methotrexate-added, n = 68) had moderate disease activity levels (mean disease activity score (DAS) of 2.6 and 2.5, respectively), whereas patients previously receiving combination therapy (n = 90) had a low disease activity level (mean DAS of 2.0). The addition of etanercept to methotrexate monotherapy resulted in a significant reduction in radiographic progression (p<0.05). Mean TSS changes in the previous year versus the current year were +1.79 versus +0.25 for the etanercept-added group (p<0.05); +0.51 versus -0.18 for the methotrexate-added group (NS) and +0.42 versus +0.24 for the combination group (NS). CONCLUSION: In these RA patients with on average moderate disease activity despite previous methotrexate monotherapy, combination treatment with etanercept and methotrexate inhibited radiographic progression and improved radiographic outcomes. These data, in conjunction with the previously published clinical data, support the use of combination therapy in RA patients with moderate disease activity.

Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine versus etanercept alone in patients with rheumatoid arthritis: a double-blind randomised 2-year study.

OBJECTIVE: To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis (RA) despite sulfasalazine therapy. METHODS: Patients were randomly assigned to etanercept (25 mg twice weekly; sulfasalazine was discontinued at baseline), etanercept plus sulfasalazine (unchanged regimen of 2-3 g/day) or sulfasalazine in a double-blind, randomised, 2-year study in adult patients with active RA despite sulfasalazine therapy. Efficacy was assessed using the American College of Rheumatology criteria, disease activity scores (DAS) and patient-reported outcomes (PRO). RESULTS: Demographic variables and baseline disease characteristics were comparable among treatment groups; mean DAS 5.1, 5.2 and 5.1 for etanercept (n = 103), etanercept plus sulfasalazine (n = 101) and sulfasalazine (n = 50), respectively. Withdrawal due to lack of efficacy was highest with sulfasalazine (26 (52%) vs 6 (6%) for either etanercept group, p<0.001). Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response, which was sustained at 2 years, than those receiving sulfasalazine: mean DAS 2.8, 2.5 versus 4.5, respectively (p<0.05); ACR 20 response was achieved by 67%, 77% versus 34% of patients, respectively (p<0.01) Overall, PRO followed a similar pattern; a clinically significant improvement in health assessment questionnaire was achieved by 76%, 78% versus 40% of patients, respectively (p<0.01). Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis (p<0.01). CONCLUSION: Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA. The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine.

[Ankylosing spondylitis in Central and Eastern Europe. Cross-sectional study on treatment modalities, disease activity and quality of life]. / Ankylosierende Spondylitis in Mittel- und Osteuropa. Querschnittsstudie zu Behandlungsmustern, Krankheitsaktivität und Lebensqualität.

OBJECTIVES: To obtain information on the profile of patients with ankylosing spondylitis (AS), disease activity, previous and current treatments, and the proportion and profile of patients treated with conventional medications but considered eligible for anti-tumour necrosis factor (TNF) therapy. METHODS: Participants were rheumatologists from seven Central and Eastern European countries who were considered experts in the treatment of AS and were to include 3-5 patients who had never received anti-TNF therapy. Rheumatologists were asked to decide whether they considered their patients candidates for anti-TNF therapy. RESULTS: A total of 1506 patients were analysed. Overall, 61% of AS patients who had never received anti-TNF therapy until the time of the survey were considered candidates for anti-TNF therapy based on the clinical judgement of their rheumatologists. This proportion ranged from 40% in Slovakia to 84% in Romania. Candidates had higher levels of disease activity and functional impairment, and they were more likely to report a lower quality of life. Only 38% of candidates fulfilled the Assessment in Ankylosing Spondylitis (ASAS) recommendations with respect to a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of at least 4 combined with previous use of at least two non-steroidal anti-inflammatory drugs, ranging from 18% in Poland to 57% in Hungary. CONCLUSION: More than half of AS patients currently treated with other medications may be eligible for anti-TNF therapy. Also, rheumatologists regarded disease activity as the determining factor for starting anti-TNF drugs, but their decision did not always fully comply with the ASAS recommendations, confirming the need for continued exchange among the medical community to increase awareness of the ASAS recommendations.

The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy.

OBJECTIVE: To determine if adding etanercept (ETN) to methotrexate (MTX) or MTX to ETN for 52 weeks in rheumatoid arthritis (RA) patients with moderate disease activity provides higher efficacy. METHODS: All patients (n = 227) received open-label ETN 25 mg subcutaneously twice-weekly and MTX orally up to 20 mg weekly for 52 weeks and had completed a 3-year study in which patients received MTX, ETN or combination therapy. Endpoints were based on Disease Activity Score (DAS) and European League Against Rheumatism (EULAR) responses. RESULTS: Patients previously receiving combination therapy (Combination group; n = 96) had a lower disease activity at baseline. The mean DAS for those previously receiving MTX (ETN-added group; n = 55) and previously receiving ETN (MTX-added group; n = 76) were in the moderate disease activity range at baseline; Combination patients had a low disease activity. The greatest increase in DAS remission rates from baseline to week 52 was in the ETN-added group (23.6% to 41.8%, p<0.01), although Combination (37.6% to 50.0%, p<0.01) and MTX-added (26.7% to 36.8%, p = NS) also demonstrated improvements. DAS low disease activity and EULAR responses showed similar results. No new safety issues were identified. CONCLUSION: RA patients who were partial responders to long-term MTX or etanercept monotherapy obtained a higher efficacy with combination therapy. Responses achieved by patients with combination therapy after 3 years in the previous study were sustained or improved during the fourth year of treatment. This trial supports the higher therapeutic effect of combination treatment with etanercept and MTX in RA patients with moderate disease activity despite monotherapy with one of the two agents.

Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis.

OBJECTIVE: The Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) is a 3-year, double-blind, multicenter study evaluating the efficacy and safety of etanercept, methotrexate, and the combination of etanercept plus methotrexate in patients with active rheumatoid arthritis (RA). The results after 1 and 2 years of the study have been previously reported. Here we provide the 3-year clinical and radiographic outcomes and safety of etanercept, methotrexate, and the combination in patients with RA. METHODS: In this randomized, double-blind, multicenter TEMPO study, 682 patients received etanercept 25 mg twice weekly, methotrexate < or =20 mg weekly, or the combination. Key efficacy assessments included the Disease Activity Score (DAS) and the DAS in 28 joints. RESULTS: Combination therapy resulted in significantly greater improvement in the DAS and in more patients with disease in remission than either monotherapy. This finding was confirmed by longitudinal analysis; patients receiving combination therapy were more than twice as likely to have disease in remission than those receiving either monotherapy. Independent predictors of remission included male sex, lower disease activity, lower level of joint destruction, and/or better physical function. Combination and etanercept therapy both resulted in significantly less radiographic progression than did methotrexate (P < 0.05). Etanercept and combination treatment were well tolerated, with no new safety findings. CONCLUSION: Etanercept plus methotrexate showed sustained efficacy through 3 years and remained more effective than either monotherapy, even after adjustment for patient withdrawal. Combination therapy for 3 years led to disease remission and inhibition of radiographic progression, 2 key goals for treatment of patients with RA.

Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison.

OBJECTIVE: To compare the efficacy and safety of etanercept and sulfasalazine, alone and in combination, in patients with active rheumatoid arthritis despite sulfasalazine treatment. METHODS: A double-blind, randomised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine (2-3 g/day) treatment. The primary end point was a 20% response by the American College of Rheumatology (ACR) criteria at 24 weeks. RESULTS: At baseline, the three treatment groups (sulfasalazine, n = 50; etanercept, n = 103; etanercept and sulfasalazine, n = 101) were comparable for demographic variables and disease activity. Lack of efficacy was the primary reason for discontinuation (sulfasalazine, n = 12; etanercept, n = 1; etanercept and sulfasalazine, n = 4; p<0.001). Significantly more patients receiving etanercept, alone or in combination (74% for each), achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine (28%; p<0.01). Similarly, more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group (p<0.01). In the groups receiving etanercept, significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone (p<0.01). The incidences of several common adverse events (headache, nausea, asthenia) were lower with etanercept alone than with the combination (p<0.05), but infections and injection site reactions were higher with etanercept alone (p<0.05). The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept. CONCLUSIONS: For all efficacy variables assessed, etanercept alone or in combination with sulfasalazine resulted in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment. All three treatments were generally well tolerated.

Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the TEMPO trial.

OBJECTIVE: To compare patient reported measures of function, health related quality of life (QoL), and satisfaction with medication among patients with rheumatoid arthritis (RA) treated with methotrexate (MTX), etanercept, or both for up to 1 year. METHODS: In a 52 week, double blind, clinical trial, patients with active RA were randomised to receive etanercept 25 mg twice weekly, methotrexate up to 20 mg weekly, or combination therapy. The Health Assessment Questionnaire (HAQ) disability index, EuroQoL health status visual analogue scale (EQ-5D VAS), patient global assessment, and patient general health VAS were administered at baseline and weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52. Satisfaction with the medication was compared at 52 weeks. RESULTS: Of 682 enrolled patients, 522 completed 52 weeks of treatment. Mean improvement from baseline in HAQ score was 0.65, 0.70, and 1.0 for MTX, etanercept, and the combination, respectively. The mean percentage and absolute improvement in the HAQ was significantly higher (p<0.01) for combination therapy than for either of the monotherapies. Combination therapy produced significantly more rapid achievement of HAQ < or =0.5 sustained for 6 months than either of the monotherapies (p<0.01). Compared with patients receiving monotherapy, those receiving combination therapy achieved a significantly better (p<0.05) health state as measured by the EQ-5D VAS (mean (SD) 63.7 (3.2), 66.8 (3.2), 72.7 (3.1) for MTX, etanercept, and the combination, respectively). Results were similar for other assessments (p<0.01). Patients in combination and etanercept groups were significantly more likely (p<0.0001, p = 0.0009, respectively) to report satisfaction with the medication. CONCLUSIONS: Combination therapy with etanercept and methotrexate improved function, QoL, and satisfaction with the medication significantly more than monotherapy.

Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results.

OBJECTIVE: To assess methods to calculate achieving and sustaining remission in a double blind randomised trial in patients with RA who received etanercept, methotrexate, or an etanercept/methotrexate combination. METHODS: Remission was defined as DAS <1.6, DAS28 <2.6, and ACR70 response. Sustaining remission was analysed in three ways: (a) analysis of sustained DAS remission, DAS28 remission, or ACR70 response continuously for 6 months; (b) analysis of sustained remission appraised through a continuity rewarded scoring system, which is the weighted sum of all intervals in the study in which patients are in DAS or DAS28 remission; or (c) longitudinal modelling of remission odds using generalised estimating equations. RESULTS: Significantly more patients treated with the etanercept/methotrexate combination reached DAS remission (37%) than those treated with either methotrexate (14%) or etanercept (18%) alone (p<0.01). Results for DAS28 and for the ACR70 response were similar. Agreement between DAS remission and DAS28 remission was good, but agreement between either of these and the ACR70 response was less. Patients in DAS or DAS28 remission had a lower level of disease activity (fewer active joints, lower ESR) than those achieving ACR70 response; the converse was seen using pain VAS. The three methods were comparable for sustainability of remission and showed significant advantage for combination therapy, which increased the number and durability of remission periods. CONCLUSIONS: DAS and DAS28 remission results were similar for assessing achieving and sustaining remission in RA, frequently differing from patients classified as ACR70 responders. The three methods of examining duration of remission produced comparable results.

Imbalance of peripheral B lymphocytes and NK cells in rheumatoid arthritis.

The study was focused on several cellular immune disorders correlated with the imbalance between peripheral blood B lymphocytes and NK cells in severe rheumatoid arthritis. By flow cytometry we calculated the proportions of T, T helper, T cytotoxic/suppressor, B lymphocytes and natural killer cells in peripheral blood. The mitogen-induced proliferation of peripheral lymphocytes was measured by tritium-labeled uridine incorporation. Experimental data highlight a connection between annomal values of the B to natural killer cells ratio and disorders of the peripheral mononuclear cells concentration. We also showed that the polyclonal proliferation capacity of peripheral lymphocytes in rheumatoid arthritis is solely related to the B to natural killer cells ratio or to the natural killer cells proportion. The study reveals a potential role of the imbalance between proportions of peripheral B lymphocytes and natural killer cells in the immune pathogenesis of rheumatoid arthritis, thus pointing out an interrelation between the adaptive and innate immune systems.

HBsAg positive secondary autoimmune active chronic hepatitis. Immunogenetic aspects.

Observations were made in a group of 120 patients with active chronic hepatitis (ACH), using demonstration of HBsAg presence, structural study of the peripheral blood mononuclear cell population by means of scanning electron microscopy (SEM) and typing of HLA-A, B and C antigens. From the whole group 22 patients were proved to have an autoimmune form of ACH secondary to infection with hepatitis B virus (HBV). The authors consider that the diagnostic value of the ratio between B and T lymphocytes (studied by SEM) is relative but the demonstration of an increased percentage of monocytomacrophage cells and the presence of "killing phenomenon" clearly reflect a more severe hepatic inflammation. A higher incidence of the HLA-Bw35-Cw4 was observed particularly in the HBsAg positive forms of ACH and in the HBsAg positive secondary autoimmune forms. The authors discuss the utility of these observations when the opportunity of corticotherapy has to be established.