Suboptimal methotrexate use in rheumatoid arthritis patients in Italy: the MARI study.

OBJECTIVES: Methotrexate (MTX) is the first choice in the treatment of rheumatoid arthritis (RA), but the doses and regimens vary significantly. For this purpose, we conducted an observational study on the use of MTX for RA in Italy (MARI study). METHODS: The MARI study included 1,327 RA patients on MTX treatment for at least 12 months, at 60 Italian rheumatology units. Concomitant medications with corticosteroids, other DMARDs or biological therapies were recorded. The clinical assessment included the Disease Activity Score 28 (DAS28) and the serological positivity for the rheumatoid factor or for the anti-citrullinated protein antibodies. RESULTS: The included patients were treated with either oral (n=288) or parenteral (n=1039) MTX. Only 15.5% of the total number of the patients was on adequate MTX dose (i.e. ≥ 15 mg for the oral route of administration and >12 mg for the parenteral one). The initially established MTX dose was modified in 37.1% of the patients, for intolerance or clinical criteria. A DAS28 remission (DAS28 <2.6) was observed only in 58.5% of the cases, while 52.9% of the patients still presenting an active form of the disease were on suboptimal doses of MTX. CONCLUSIONS: The weekly dose of MTX prescribed for the treatment of RA is often suboptimal, even in conditions of inadequate control of the disease activity. The recommendations for the use of MTX in RA patients should take into account the efficacy and tolerability data derived from its use in real clinical practice.

Safety of rituximab in the routine treatment of rheumatoid arthritis in Italy in patients refractory to anti-TNFa drugs: results from the observational retrospective-prospective RUBINO study.

The paper reports the results from the observational retrospective-prospective RUBINO study conducted in Italy to assess the safety of rituximab in the treatment of rheumatoid arthritis (RA) in routine clinical practice. The percentage of patients who manifested at least one grade 3 or 4 adverse event (AE) assessed by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v.3) during the observation period (primary objective) was evaluated. The percentage of patients manifesting a severe AE (SAE), clinical response to rituximab treatment, clinical remission according to disease activity score for 28 joints (DAS28) criteria, markers of disease and quality of life were also assessed. Fifty-three Italian rheumatology centers took part in the study. Patients with a diagnosis of RA and inadequate response to anti-tumor necrosis factor b (anti-TNFa) drugs were enrolled. Participating patients had previously received at least one cycle of rituximab, and treatment was still ongoing at the time of recruitment. Out of 205 patients enrolled, 60% manifested no form of AE, 14.2% had at least one grade 3 or 4 AE, and 11.2% patients reported an SAE. The overall percentage of patients manifesting AEs (40%) was lower compared to the DANCER (81% and 85%), REFLEX (85%) and RESET (85% and 69%) studies, but higher than that observed in the CERERRA registry (from 10.2% to 13.9%). This difference may be due to the shorter observation period applied in the CERERRA registry (only 12 months) compared to the RUBINO study (up to 3 years). All parameters of RA activity (erythrocyte sedimentation rate, C-reactive protein, health assessment questionnaire score, DAS28) improved significantly during the study.

153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients.

BACKGROUND: Bone metastatic patients with osteosarcoma have a very poor prognosis. Targeted radiation therapy has been pursued as a valid alternative. The primary end point of this study was progression-free survival (PFS) at 4 months. PATIENTS AND METHODS: Twenty-two osteosarcoma patients were treated with Samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) at various dosages. Administered activities ranged from 150 (3 mCi/kg) to 1140 MBq/kg (30 mCi/kg). Autologous hematopoietic stem cell infusion was carried out on day 14 after the (153)Sm-EDTMP infusion. RESULTS: The median PFS was 61 days (18-436 days) and the median overall survival (OS) was 189 days (31-1175 days). PFS and OS for the entire patient population were 32% [95% confidence interval (CI) 16-50] and 76% (95% CI 52-89) at 4 months, respectively. No statistical differences emerged according to 153Sm-EDTMP administered or 24-h retained activity. One-month pain palliation was only observed in a minority of subjects and in none at 4 months. CONCLUSIONS: Based on our series, the PFS is dramatically short even when higher activity of (153)Sm-EDTMP is administered. This would mean that, even at high level, 153Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients.

Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis.

OBJECTIVES: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc). METHODS: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression. RESULTS: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction. CONCLUSION: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective.

Study on the possible role of the -174G>C IL-6 promoter polymorphism in predicting response to rituximab in rheumatoid arthritis.

OBJECTIVE: Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. The -174G>C interleukin-6 (IL-6) promoter polymorphism was investigated in RA patients treated with rituximab (RTX), being IL-6 a key cytokine for B cell survival and proliferation, thus possibly implicated in rituximab efficacy. METHODS: The study was conducted in a real-life retrospective cohort of 142 unselected RA patients (120F/22M) treated with RTX and referred to 7 rheumatologic centres in the north of Italy. One hundred and thirteen (79.6%) patients were rheumatoid factor (RF)-positive and 112 (78.9%) were anti-CCP antibodies positive. The response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR criteria (DAS28) and the ACR criteria. The IL-6 -174G>C promoter polymorphism was analyzed by RFLP following previously reported methods. RESULTS: Lack of response to RTX at month +6 by EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (9/21, 42.8%), than in the GC/GG patients (23/121, 19.0%) (OR 3.196, 95% CI=1.204-8.485; p=0.0234). Similar results were found when evaluating the response by ACR criteria. No differences were found in RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status according to the different IL-6 -174 genotypes. CONCLUSION: IL-6 promoter genotyping may be useful to better plan treatment with RTX in RA. Larger replication studies are in course to confirm these preliminary results.

Prevention of intrahepatic recurrence by adjuvant (131)iodine-labeled lipiodol after resection for hepatocellular carcinoma in HCV-related cirrhosis.

AIM: To evaluate the impact of postoperative injection into the hepatic artery of 131-iodine-labeled lipiodol on disease-free and overall survival rates in patients who underwent liver surgical resection for hepatocellular carcinoma. METHODS: Ten consecutive patients with HCV (hepatitis C virus)-related cirrhosis who underwent liver surgical resection for hepatocellular carcinoma were treated with adjuvant injection of 131-iodine-labeled lipiodol. They were matched with 20 HCV-positive cirrhotic controls who underwent liver resection alone; patients were paired in terms of age, Child-Pugh class, tumor size, microscopic vascular invasion, tumor histological pattern, presence of satellite nodules and type of surgical resection. Recurrence was defined as the development of a new hypervascularizated nodule in the liver. RESULTS: No significant differences were found between the two groups in clinical, biologic and histologic characteristics, except a lower platelet count in the control group. None of the treated patients developed an intrahepatic recurrence until the 15th month from liver resection, whereas recurrences occurred in nine of the 20 patients in the control group (p=0.01). From 18 months onwards, recurrences appeared also in the treated patients, and after 36 months of follow-up both recurrence rate and overall survival were not significantly different between the two groups. CONCLUSIONS: Intrahepatic injection of 131-iodine-labeled lipiodol improves the disease-free survival rate following liver resection of hepatocellular carcinoma in the short term up to 15 months; this advantage fades, however, away after 36 months.

Red marrow and blood dosimetry in (131)I treatment of metastatic thyroid carcinoma: pre-treatment versus in-therapy results.

Treatment with radioiodine is a standard procedure for patients with well-differentiated thyroid cancer, but the main approach to the therapy is still empiric, consisting of the administration of fixed activities. A predictive individualized dosimetric study may represent an important tool for physicians to determine the best activity to prescribe. The aim of this work is to compare red marrow and blood absorbed dose values obtained in the pre-treatment (PT) dosimetry phase with those obtained in the in-treatment (IT) dosimetry phase in order to estimate the predictive power of PT trial doses and to determine if they can be used as a decision-making tool to safely administer higher (131)I activity to potentially increase the efficacy of treatment. The PT and IT dosimetry for 50 patients has been evaluated using three different dosimetric approaches. In all three approaches blood and red marrow doses, are calculated as the sum of two components, the dose from (131)I activity in the blood and the dose from (131)I activity located in the remainder of the body (i.e. the blood and whole-body contributions to the total dose). PT and IT dose values to blood and red marrow appear to be well correlated irrespective of the dosimetric approach used. Linear regression analyses of PT and IT total doses, for blood and red marrow, and the whole-body contribution to these doses, showed consistent best fit slope and correlation coefficient values of approximately 0.9 and 0.6, respectively: analyses of the blood dose contribution to the total doses also yielded similar values for the best fit slope but with correlation coefficient values of approximately 0.4 reflecting the greater variance in these dose estimates. These findings suggest that pre-treatment red marrow dose assessments may represent an important tool to personalize metastatic thyroid cancer treatment, removing the constraints of a fixed activity approach and permitting potentially more effective higher (131)I activities to be safely used in-treatment.

Comparison of mathematical models for red marrow and blood absorbed dose estimation in the radioiodine treatment of advanced differentiated thyroid carcinoma.

Metastatic and recurrent differentiated thyroid carcinoma is preferably treated with (131)I, whose administered activity is limited by red marrow (RM) toxicity, originally correlated by Benua to a blood absorbed dose higher than 2 Gy. Afterward a variety of dosimetric approaches has been proposed. The aim of this work is to compare the results of the Benua formula with the ones of other three blood and RM absorbed dose formulae. Materials and methods have been borrowed by the dosimetric protocol of the Italian Internal Dosimetry group and adapted to the routine of our centre. Wilcoxon t-tests and percentage differences have been applied for comparison purposes. Results are significantly different (p < 0.05) from each other, with an average percentage difference between Benua versus other results of -22%. The dosimetric formula applied to determine blood or RM absorbed dose may contribute significantly to increase heterogeneity in absorbed dose and dose-response results. Standardization should be a major objective.

Thyroid cancer prevalence after radioiodine treatment of hyperthyroidism.

UNLABELLED: The definitive treatment of hyperthyroidism in Europe is quite different from that in the United States. In Europe, the surgical approach is often preferred and considered safer than radioiodine treatment. European doctors usually prefer to surgically remove the thyroid and perform a pathologic examination of it. They consider it to be an essential diagnostic tool to identify possible diseases that might be associated with hyperthyroidism and even to detect the rare thyroid tumors that might be associated with thyroid hyperfunction. The aim of this study was to evaluate whether radioiodine therapy could be a risk factor for the misdiagnosis of thyroid cancer. METHODS: We performed a retrospective revision of data we collected from 6647 patients (1171 [17.5%] men, 5476 [82.5%] women), all of whom underwent 1311 therapy for hyperthyroidism from 1970 to 1997. Of the whole group, 6.5% were younger than 40 y, 33.5% were 40-60 y old, and 60% were older than 60 y. Moreover, 5061 (76%) patients had either an autonomously functioning node or a toxic multinodular goiter. The other 1586 (24%) patients had Graves' disease. RESULTS: After treatment, thyroid cancer was discovered in 10 (0.15%) patients, none of whom belonged to the group of patients with Graves' disease. Five of these patients were treated during a period from 1970 to 1980, when sonography was not routinely available. The incidence of thyroid cancer in the series of radioiodine-treated patients (150/100,000 over a 27-y period) was not significantly different from its incidence in the general population. The expected rate is 124.88 per 100,000 over a 27-y period. CONCLUSION: An accurate preliminary evaluation (clinical examination, sonography, and cytologic evaluation of fine-needle aspiration) is fundamental for a proper choice between radioiodine and surgical therapy.

Sentinel lymph node and breast cancer staging: final results of the Turin Multicenter Study.

AIM OF THE STUDY: Validation of the sentinel node (SN) technique in breast cancer by means of lymphoscintigraphy. MATERIALS AND METHODS: From December 1996 to January 1999 102 T1-T2 breast carcinoma cases were recruited in Turin. 99mTc-human serum albumin colloids were injected subdermally the day before surgery (mean activity, 5.2 +/- 2.5 MBq). Scintigraphic imaging was performed after injection. After identification of the SN during surgery by a hand-held gamma probe, the SN was excised and sent for histologic examination. SN histology was compared with that of other axillary nodes. RESULTS: The SN detection rate was 86.3%; among 88 cases with an identified SN, 37 (42%) had axillary metastases; the SN was metastatic in 35 cases (sensitivity, 94.6%); in 51.3% of pN+ cases (19/37) the SN was the only metastatic site. In two of the 53 negative SNs, SN histology did not match with that of the remaining axilla (negative predictive value, 96.2%; staging accuracy, 97.7%). CONCLUSIONS: Our results agree with those reported in the literature; however, except in clinical trials and experienced structures axillary lymph node dissection should not be abandoned when mandatory for prognostic purposes, considering that at present SN biopsy alone is not completely accurate for axillary staging, especially in the absence of an adequate learning period.

[Renal damage in rheumatoid arthritis]. / Il danno renale in corso di artrite reumatoide.

Renal damage is not uncommon in rheumatoid arthritis, but the causative role of the disease per se is not well defined yet. In this paper the updated literature data are reported and our own experience as well. In particular, we describe renal syndromes associated with non-steroidal antiinflammatory drugs, remission-inducing agents (gold and penicillamine) and cytotoxic drugs, secondary amyloidosis, systemic rheumatoid vasculitis, glomerular and tubulo-interstitial nephritis not related to drug therapy.

[Wegener's granulomatosis. Diagnosis and follow-up of 7 cases]. / Granulomatosi di Wegener. Diagnosi e follow-up di 7 casi.

Wegener's granulomatosis (WG) is a rare small vessels necrotizing and granulomatous systemic vasculitis which usually affects the respiratory-tract and the kidneys. Diagnosis is often difficult, but has become easier with antineutrophil cytoplasmic antibodies (ANCA) detection that may justify a more aggressive biopsy policy also in the elderly. Classic treatment with steroids and oral cyclophosphamide (CY) has proven to be of benefit, but side-effects are severe and frequent and the search for less toxic therapeutic schemes should be encouraged. We treated with intravenous pulses of CY (1 g/m2 monthly for 6 months, every two months for the following 6 and quarterly for another year) 5 of 7 patients with WG recently admitted to our institution. We obtained a quick, complete response in 4 of these patients, with no side effects, nor relapses, after a mean follow-up of 17 months. The only patient who did not respond was identified soon after the beginning of the treatment because of a poor reduction of ESR and could be shifted to oral administration of CY successfully. From our still limited experience CY intravenous pulses have proven to be safe and effective enough to advice its use as the first-choice treatment for WG.

[Considerations on atypical acute bronchopneumopathies]. / Considerazioni sulle broncopneumopatie acute atipiche.

The cases were studied of 109 patients admitted to the 2nd General Medical Division of the Umberto I Hospital in Turin in the course of a year. The study revealed 99 bacterial infections and 10 atypical forms including 7 mycoplasma pneumoniae and 3 virus infections. The importance of suspecting atypical pneumopathies is therefore emphasised and despite the technical difficulties that may at times arise, tests for the less common aetiological agents are recommended.

[Importance of prolactinemia and IgA-transferrin ratio in chronic alcoholism and alcoholic hepatopathies]. / Importanza della prolattinemia e del rapporto IgA-transferrina nell'etilismo cronico e nell'epatopatia etilica.

Levels of prolactinaemia, IgA and transferrin and the ratio between the two latter were measured in 20 male chronic alcoholics and a second group of controls in order to verify the diagnostic importance of such measurements. In partial conflict with reports in the literature, it is concluded that prolactinaemia measurement is not particularly important. The evaluation of the IgA-transferrin ratio, on the other hand, is judged to be useful for the diagnosis of alcohol-induced hepatopathologies.

[Clinical trial of a new broad-spectrum cephalosporin: HR 756 (cefotaxime)]. / Sperimentazione clinica di una nuova cefalosporina ad ampio spettro: HR 756 (cefotaxime).

A second-generation cephalosporin (cephotaxime) with a marked resistance to beta-lactamase, a very broad spectrum, and remarkably low renal toxicity was used to treat 47 patients with respiratory, urinary and other infections. The results were excellent in 89.2% and good in 8.5%. The antibiotic proved effective even against germs that are usually resistant to cephalosporins (Pseudomonas, Proteus, Serratia and Enterobacteriaceae). Bacteriuria disappeared in all cases of urinary infection. Local and general tolerance was excellent in all cases but one. Renal tolerance was also excellent in patients with chronic renal failure, for whom the daily dose can be usefully reduced and a check on renal function should be kept.

[Survival and therapy of multiple myeloma. Apropos of 56 observed cases]. / Considerazioni su sopravvivenza e terapia del mieloma multiplo. A proposito di 56 casi di nostra osservazione.

56 cases of myeloma observed since 1956 are reviewed and it is noted that course, prognosis and survival have changed in relation to the improvement in diagnostic procedures and therapeutic aids. The recent introduction of polychemotherapeutic approaches based on theoretical considerations has not yet been fully vetted in the clinic although a higher percentage of remissions compared to that obtained by monochemotherapy would seem to be confirmed. Personal experience with a new polychemotherapeutic schema in advanced myeloma resistant to monochemotherapy + prednisone is reported.

[Andersson's phenomenon in HLA-B27 negative ankylosing spondylitis]. / Fenomeno di andersson in spondilite anchilosante HLA-B27 negativa.

A computed tomography (CT) and conventional radiography study is reported in a case of HLA-B27 negative ankylosing spondylitis. The value of CT in comparison with conventional radiography in evaluation of anatomic alterations is determined.

An association of primary hyperparathyroidism and non medullary thyroid carcinoma.

A 40-year-old woman was admitted because of long-lasting asymptomatic hypercalcaemia. About 2 years earlier she underwent thyroidectomy and further 131 I therapy because of well-differentiated non medullary thyroid carcinoma. On admission biochemical data and hormonal values (serum calcium, serum phosphorus, i-PTH) were consistent with primary hyperparathyroidism; ultrasonography, computed tomography, thallium-technetium scintiscanning disclosed right paratracheal mass; on surgical procedure a right parathyroid adenoma was removed. The coexistence of non medullary thyroid carcinoma and primary hyperparathyroidism is rare: the prior 131 I therapy might be linked to subsequent development of parathyroid adenoma.

Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database.

OBJECTIVE: To determine the prevalence of and independent factors associated with joint involvement in a large population of patients with systemic sclerosis (SSc). METHODS: This study was cross-sectional, based on data collected on patients included in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) registry. We queried this database to extract data regarding global evaluation of patients with SSc and the presence of any clinical articular involvement: synovitis (tender and swollen joints), tendon friction rubs (rubbing sensation detected as the tendon was moved), and joint contracture (stiffness of the joints that decreased their range of motion). Overall joint involvement was defined by the occurrence of synovitis and/or joint contracture and/or tendon friction rubs. RESULTS: We recruited 7286 patients with SSc; their mean age was 56 +/- 14 years, disease duration 10 +/- 9 years, and 4210 (58%) had a limited cutaneous disease subset. Frequencies of synovitis, tendon friction rubs, and joint contractures were 16%, 11%, and 31%, respectively. Synovitis, tendon friction rubs, and joint contracture were more prevalent in patients with the diffuse cutaneous subset and were associated together and with severe vascular, muscular, renal, and interstitial lung involvement. Moreover, synovitis had the highest strength of association with elevated acute-phase reactants taken as the dependent variable. CONCLUSION: Our results highlight the striking level of articular involvement in SSc, as evaluated by systematic examination in a large cohort of patients with SSc. Our data also show that synovitis, joint contracture, and tendon friction rubs are associated with a more severe disease and with systemic inflammation.