Assessing the cost-effectiveness of biologic agents for the management of moderate-to-severe rheumatoid arthritis in anti-TNF inadequate responders in Italy: a modelling approach.

OBJECTIVES: The objective of this study is to assess cost-effectiveness of different biologic strategies in patients with moderate-to-severe active RA after an insufficient response to anti-TNF agents within the context of the Italian healthcare system. METHODS: Simulation models were developed allowing for potential biologic therapy switch at each 6-month time point in case of an insufficient response to the previous biologic agent. Biologic treatments included etanercept, abatacept, adalimumab, rituximab or infliximab. Effectiveness criteria for these models were defined as achieving a state of low disease activity (LDAS) [DAS28 ≤3.2] or remission (RS) [DAS28<2.6]. Monte-Carlo simulations were performed for each sequence to manage data variability. RESULTS: The biologic treatment sequence using abatacept after an insufficient response to a first anti-TNF agent appeared significantly more efficacious over 2 years (102 days in LDAS) compared to rituximab (82 days in LDAS). The sequence using abatacept after 2 anti-TNF agents appeared significantly more efficacious (63 days in LDAS) compared to using a third anti-TNF agent (32 days in LDAS). Mean cost-effectiveness ratios showed significantly lower costs per day in LDAS with abatacept used after one anti-TNF agent (€376) compared to rituximab (€456). The sequence using abatacept after 2 anti-TNF agents was also more cost-effective (€642 per day in LDAS) versus a sequential use of anti-TNF therapies (€1164 per day in LDAS). All comparisons were confirmed when using the remission effectiveness criteria. CONCLUSIONS: The results of this health economics modelling study suggest that the biologic treatment sequence using abatacept after an insufficient response to a first anti-TNF agent appears significantly more effective and cost-effective versus a similar sequence using rituximab for achieving remission or LDAS. The results also indicate that in the case of an insufficient reponse to 2 anti-TNF agents, abatacept appears more effective and cost-effective than using a 3rd anti-TNF agent.

Disease activity assessment of rheumatoid arthritis in daily practice: validity, internal consistency, reliability and congruency of the Disease Activity Score including 28 joints (DAS28) compared with the Clinical Disease Activity Index (CDAI).

OBJECTIVE: The Disease Activity Score including 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI) were developed in order to provide a quantifiable measure of rheumatoid arthritis (RA) activity. The aim of this study was to evaluate the validity and internal consistency reliability for DAS28 and CDAI in patients with RA seen by rheumatologists in usual clinical care. We also compared proposed categories of high, moderate, and low activity and remission according to both scores. PATIENTS AND METHODS: A sample of 2864 RA patients (2267 female, 597 male; mean age 58.5 yr, range 18-88 yr) were enrolled in this cross-sectional community-based study. Disease activity was assessed in each patient based on DAS28 and CDAI. Patients completed the Health Assessment Questionnaire (HAQ). Statistical evaluation was carried out by applying the Cronbach's values and principal component analysis (internal consistency reliability), the Pearson's coefficients, ANOVA and kappa statistic (convergent validity) and receiver operating characteristic (ROC) curve analysis (discriminant validity). RESULTS: Internal consistency testing of both scores indicated a reasonable difference, with Cronbach's alpha slightly higher for the DAS28. Interestingly, factor analysis revealed that the DAS28 constitutes a monocomponent measure in RA. Linear regression analysis showed a significant correlation between DAS28 and CDAI (p<0.0001). In addition, the DAS28 and CDAI were well correlated with HAQ (both at p level of <0.0001). The discriminatory power of both indices was good, without significant difference, but our results showed wide differences in both moderate/high disease activity and remission percentages (k=0.418). CONCLUSIONS: DAS28 and CDAI are valid and simple acceptable ways to measure RA activity in the clinical practice, but disease activity categorized by these indices differ considerably. Further research is needed to resolve this issue.

Fibromyalgia syndrome: preventive, social and economic aspects.

There many open questions concerning the concept of primary prevention in FM. Diagnostic or classification criteria are not universally accepted, and this leads to difficulties in establishing the onset and duration of the disease. In the case of FM, primary prevention may consist of the immediate care of acute pain or treatment for affective disturbances as we do not have any specific laboratory or instrumental tests to determine risk factors of the disease. The goal of secondary prevention is early detection of the disease when patients are largely asymptomatic and intervention improves outcome. Screening allows for identification of an unrecognized disease or risk factor, which, for potential FM patients, includes analysis of tender points, Fibromyalgia Impact Questionnaire (FIQ), pain location and intensity, and fatigue and sleep complaints. Tertiary prevention inhibits further deterioration or reduces complications after the disease has developed. In FM the aim of treatment is to decrease pain and increase function via multimodal therapeutic strategies, which, in most cases, includes pharmacological and non-pharmacological interventions. Patients with FM are high consumers of health care services, and FM is associated with significant productivity-related costs. The degree of disability and the number of comorbidities are strongly associated with costs. An earlier diagnosis of FM can reduce referral costs and investigations, thus, leading to a net savings for the health care sector. However, every social assessment is closely related to the socio-economic level of the general population and to the legislation of the country in which the FM patient resides.

Fibromyalgia syndrome: definition and diagnostic aspects.

Ever since it was first defined, fibromyalgia (FM) has been considered one of the most controversial diagnoses in the field of rheumatology, to the point that not everybody accepts its existence as an independent entity. The sensitivity and specificity of the proposed diagnostic criteria are still debated by various specialists (not only rheumatologists), whose main criticism of the 1990 American College of Rheumatology criteria is that they identify subsets of particular patients that do not reflect everyday clinical reality. Furthermore, the symptoms characterising FM overlap with those of many other conditions classified in a different manner. Over the last few years, this has led to FM being considered less as a clinical entity and more as a possible manifestation of alterations in the psychoneuroendocrine system (the spectrum of affective disorders) or the stress reaction system (dysfunctional symptoms). More recently, doubts have been raised about even these classifications; and it now seems more appropriate to include FM among the central sensitisation syndromes, which identify the main pathogenetic mechanism as the cause of skeletal and extra-skeletal symptoms of FM and other previously defined "dysfunctional" syndromes.

Etiopathogenetic mechanisms of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a common chronic condition of widespread pain with causal mechanisms that are largely unknown. It is characterized by moderate to severe musculoskeletal pain and allodynia, but its pathogenesis appears confined to the nociceptive structures of the central nervous system. FMS is often triggered by negative environmental influences, especially if they occur in childhood. In a fetus, these environmental triggers may influence the development of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPA). Increasing evidence supports the comorbidity of psychological conditions including depression, panic disorders, anxiety, and post-traumatic stress disorder (PTSD). Recent evidence suggests that genetic factors may play a role in the pathogenesis of FMS. Central sensitization has long been associated with FMS pain. It describes enhanced excitability of dorsal horn neurons, which leads to transmission of altered nociceptive information to the brain. Understanding of pathogenetic pathways in FMS has advanced beyond observing patient responses to neurophysiologically targeted therapies and basic research.

Non pharmacological treatments in fibromyalgia.

Fibromyalgia is a complex syndrome associated with significant impairment in quality of life and function and with substantial financial costs. Once the diagnosis is made, providers should aim to increase patients' function and minimize pain. Fibromyalgia patients frequently use alternative therapies, strongly indicating both their dissatisfaction with and the substantial ineffectiveness of traditional medical therapy, especially pharmacological treatments. At present, pharmacological treatments for fibromyalgia have a rather discouraging cost/benefit ratio in terms of poor symptom control and high incidence of side effects. The interdisciplinary treatment programs have been shown to improve subjective pain with greater success than monotherapy. Physical therapies, rehabilitation and alternative therapies are generally perceived to be more "natural," to have fewer adverse effects, and in some way, to be more effective. In this review, physical exercise and multimodal cognitive behavioural therapy are presented as the more accepted and beneficial forms of nonpharmacological therapy.

Symptoms and signs in fibromyalgia syndrome.

Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population. Chronic widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headaches, and mood disorders. The etiology of FM is not completely understood and the syndrome is influenced by factors such as stress, medical illness, and a variety of pain conditions. Establishing diagnosis may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. A unifying hypothesis is that FM results from sensitization of the central nervous system; this new concept could justify the variety of characteristics of the syndrome. FM symptoms can be musculoskeletal, non-musculoskeletal, or a combination of both; and many patients will also experience a host of associated symptoms or conditions. The ACR classification criteria focus only on pain and disregard other important symptoms; but three key features, pain, fatigue and sleep disturbance, are present in virtually every patient with FM. Several other associated syndromes, including circulatory, nervous, digestive, urinary and reproductive systems are probably a part of the so called central sensitivity or sensitization syndrome. A minority subgroup of patients (30-40%) has a significant psychological disturbance. Psychological factors are an important determinant of any type of pain, and psychological comorbidity is frequent in FM. Psychiatric disorders most commonly described are mood disorders, but psychiatric illness is not a necessary factor in the etiopathogenesis of FM.

Fibromyalgia syndrome: the pharmacological treatment options.

Pharmacological treatment has been gradually enriched by a variety of compounds; however, no single drug is capable of fully managing the constellation of fibromyalgia (FM) symptoms. Currently, it is not possible to draw definite conclusions concerning the best pharmacological approach to managing FM because results of randomized clinical trials present methodological limitations and therapeutic programs are too heterogeneous for adequate comparison. However, a variety of pharmacological treatments including antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have been used to treat FM with varying results. In this review, we will evaluate those pharmacological therapies that have produced the most significant clinical results in treating FM patients. The nature of FM suggests that an individualized, multimodal approach that includes both pharmacologic and nonpharmacologic therapies seems to be the most appropriate treatment strategy to date.

The evaluation of the fibromyalgia patients.

Fibromyalgia (FM) is a rheumatic disease characterized by musculoskeletal pain, chronic diffuse tension and/or stiffness in joints and muscles, easy fatigue, sleep and emotional disturbances, and pressure pain sensitivity in at least 11 of 18 tender points. At present, there are no instrumental tests or specific diagnostic markers for FM; in fact, many of the existing indicators are significant for research purposes only. Many differential diagnoses may be excluded by an extensive clinical examination and patient history. Considering overlap of FM with other medical conditions, the treating physicians should be vigilant: chest-X-rays and abdominal ultrasonography are the first steps of general evaluation for all the patients with suspected FM. Functional neuroimaging methods have revealed a large number of supraspinal effects in FM, a disorder mediated by mechanisms that are essentially unknown. Many treatments are used in FM patients, but evaluating their therapeutic effects in FM is difficult because the syndrome is so multifaceted. To address the identification of core outcome domains, the Initiative on IMMPACT and OMERACT workshop convened a meeting to develop consensus recommendations for chronic pain clinical trials.

[Italian consensus on EULAR recommendations 2005 for the management of hip osteoarthritis]. / Consensus italiana sulle raccomandazioni EULAR 2005 per il trattamento dell'artrosi dell'anca.

The recommendations for the management of osteoarthritis (OA) of the hip were proposed by EULAR in 2005. Among the most important objectives of the expert charged to provide these recommendations were their wide dissemination and implementation. Thus, the information generated can be used by each individual country to produce their own set of management guidelines and algorithms for treatment in primary care. According with that previously executed for the EU-LAR recommendation 2003 for the knee, the Italian Society of Rheumatology (SIR) has organised a Consensus on the EULAR recommendations 2005 for the management of hip OA. To obtain an acceptability as large as possible, the group of experts was composed by many physicians interested in the management of hip OA, including Orthopaedics, Rheumatologists, Physiatrists, and General Practitioners. Main aim of the Consensus was to analyse the acceptability and applicability of the recommendations according to own experience and local situations in the Italy. The results of this Consensus have demonstrated that a large majority of the EULAR recommendations are endorsed by the Italian experts. Furthermore, the final document of the Italian Consensus clearly indicated the need that the specialists involved in the management of hip OA strongly encourage the dissemination of the EULAR 2005 recommendations also in Italy.

[Psoriatic arthritis: epidemiological and clinical aspects in a cohort of 1.306 Italian patients]. / Artrite psoriasica: aspetti epidemiologici e clinici in 1.306 pazienti afferenti a 37 strutture reumatologiche italiane.

Because there is the impression that psoriatic arthritis is a composite disorder with mild forms close to more severe and aggressive ones, we conducted a multicenter study with the aim of characterizing disease expression in a large cohort of Italian patients. One-thousand-three-hundred-six patients fulfilled inclusion criteria and were analyzed in this study. Psoriasis antedated the onset of arthritis in the majority of the cases (67.7%). More rare was inverse or simultaneous onset which occurred in 17.3% and 15.0% of the cases, respectively. Peripheral articular involvement (mono-oligo or polyarthritis) was recorded in 88.7% of the cases while spondylitis occurred in 11.3%. Peripheral enthesopathies were found in 28.1% of the cases with a marked occurrence in patients with axial involvement (64.5% vs 35.5% in oligo or polyarthritis). Abnormal levels of ESR and CRP respectively occurred in 52.2% and in 52.6% of the cases, while rheumatoid factor was detected in 5.0% of the cases. On the basis of distribution of joint involvement, symmetry and presence of peripheral enthesopathies we recognized three clusters of arthritis. Patients included in Cluster 1 and Cluster 2 showed a severe form of polyarthritis in most of the cases (82.9%), with increased serum levels of inflammatory indices in more than 85% of the cases. Almost all the hospitalized patients (97.1%) were included in this two clusters. They markedly assumed steroids and methotrexate or another DMARD. About half of the patients (51.1%) included in Cluster 3 showed mono-oligo articular involvement. Serum inflammatory indices were increased in 20.8% of the cases while hospitalization occurred only in 2.9% of the cases and NSAIDs were the treatment of choice. The evidence in our country of a large prevalence of severe forms of arthritis needing specific and aggressive approach outlines the requirement of an intense educational action aimed at increasing the awareness of this condition.

[Italian consensus on Eular 2003 recommendations for the treatment of knee osteoarthritis]. / Consensus italiana sulle raccomandazioni dell'EULAR 2003 per il trattamento dell'artrosi del ginocchio.

The recommendations for the management of osteoarthritis (OA) of the knee firstly proposed by the EULAR in 2000, have been updated in 2003. One of the most important objectives of the expert charged to provide these recommendations was their dissemination. Thus, the information generated may be used by each individual country to produce their own set of management guidelines and algorithms for treatment in primary care. The Italian Society of Rheumatology (SIR) and the Italian League against Rheumatism (LIMAR) have organised a Consensus on the EULAR recommendations 2003 with the aim to analyse their acceptability and applicability according to our own experience and local situations in the Italy. The results of this Consensus have demonstrated that a large majority of the EULAR recommendations are endorsed by the Italian experts. Furthermore, the final document of the Italian Consensus clearly indicated the need that specialists involved in the management of knee OA strongly encourage the dissemination of the EULAR 2003 recommendations also in Italy.

[Farmacoeconomic impact of anti-TNF-alpha]. / Impatto farmacoeconomico degli anti-TNF-alpha.

The anti-TNF-alpha are undoubtedly an efficacious cure in the treatment of rheumatoid arthritis, but their costs are so high that a thorough pharmacoeconomical evaluation is needed in order to identify the specific conditions in which their use is to be considered convenient. For this reason there are related the most important experiences that have studied the cost-efficacy and cost-utility relationships of anti-TNF-alpha drugs, which have been made marketable in Italy. The data available, unfortunately, are too various to allow a final settlement of the chart of convenience between the different therapeutic alternatives. Moreover the socio-medical reality in Italy is so much different from the ones in other countries that it is impossible to try and use the foreign experiences. In a country of high social commitment like Italy, a fair judgment can thereafter be made only when the issue is considered related to our society, taking in account the summation of the medical costs endured by the National Health System, the patient's expenses and the ones that are a consequence of the loss of productivity.

Direct and indirect costs of osteoarthritis of the knee.

BACKGROUND: Rheumatic diseases have an economic impact of 1-2.5% of GDP in industrialized countries and osteoarthritis is the most common joint disorder. Osteoarthritis of the knee is especially common and is a major cause of disability requiring extensive utilization of health care resources. OBJECTIVE: To estimate the burden of osteoarthritis of the knee in Italy, we studied retrospectively a cohort of 254 patients over a period of 12 months in 2000-2001. METHODS: Twenty-nine rheumatology institutes took part in the study. A bottom-up approach was used, analytically measuring pro capita consumption. We considered medical (hospitalization, diagnosis, and therapies) and non-medical costs (transport, temporary caregivers, and auxiliary devices) as direct costs. We calculated losses of productivity borne by patients and caregivers, and informal care provided by caregivers as indirect costs. RESULTS: Direct costs came to Euros 934 per patient per year: Euros 233 were spent on hospitalization, Euros 209 on diagnostic procedures (56% on visits and 44% on instrumental and laboratory tests), Euros 146 on therapy (58% on physiotherapy and 42% on drugs), and Euros 346 on non-medical costs (73% on salaries to temporary caregivers, 14% on transport, and 13% on auxiliary devices). It is interesting to point out that at least 37% of costs were charged directly to patients. Indirect costs were almost 30% higher and came to Euros 1236 per patient per year: 31% was due to loss of productivity of patients, 60% due to informal care provided by primary caregivers, and 9% by other caregivers. CONCLUSIONS: This study confirms that the direct and indirect costs attributable to osteoarthritis of the knee are substantial.

Reliability and validity of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index in Italian patients with osteoarthritis of the knee.

OBJECTIVE: The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis (OA) Index is a tested questionnaire to assess symptoms and physical functional disability in patients with OA of the knee and the hip. We adapted the WOMAC for the Italian language and tested its metric properties in 304 patients with symptomatic OA of the knee. METHODS: Three hundred and four consecutive patients, attending 29 rheumatologic outpatient clinic in northern, central, and southern Italy, were asked to answer two disease-specific questionnaires (WOMAC and Lequesne algofunctional index) and one generic instrument (Medical Outcomes Study SF-36 Health Survey-MOS SF-36). A sample of 258 patients was readministered the WOMAC 7-10 days after the first visit and the structured interview, which also assessed demographic and other characteristics. Internal consistency was assessed using Cronbach's alpha, reliability using intraclass correlation coefficients (ICCs), and construct and discriminant validity using Spearman's correlations, Wilcoxon rank sum test, and Kruskal-Wallis test. RESULTS: All WOMAC subscales (pain, stiffness, and physical function) were internally consistent with Cronbach's coefficient alpha of 0.91, 0.81, and 0.84, respectively. Test-retest reliability was satisfactory with ICCs of 0.86, 0.68, and 0.89, respectively. In comparison with the SF-36, the expected correlations were found when comparing items measuring similar constructs, supporting the concepts of convergent construct validity. Very high correlations were also obtained between WOMAC scores and Lequesne OA algofunctional index. WOMAC physical function, but not WOMAC stiffness and pain subscales, was weakly associated with radiological OA severity (P=0.03). Also, WOMAC pain score was inversely correlated (P=0.01) with years of formal education. Examination of discriminant validity showed that the scores on the WOMAC and SF-36 followed hypothesized patterns: the WOMAC discriminated better among subjects with varying severity of knee problems, whereas the SF-36 discriminated better among subjects with varying levels of self-reported health status and comorbidity. CONCLUSION: The Italian version of WOMAC is a reliable and valid instrument for evaluating the severity of OA of the knee, with metric properties in agreement with the original, widely used version.

A multicenter cost-of-illness study on rheumatoid arthritis in Italy.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic and disabling disease frequently leading to physical and psychological dependence, with considerable economic consequences. The aim of our study was to perform a cost-of-illness analysis for RA according to the four different levels of functional RA severity. METHODS: Direct costs (hospitalisations, treatments, diagnostics and the non-medical costs), indirect costs (productivity losses and informal care), and intangible costs (deterioration in the quality of life of patients, their families and friends assessed by the Medical Outcome Survey Short Form and the Stanford Health Assessment Questionnaire) were measured in 200 RA patients. RESULTS: The social costs--direct plus indirect costs--increased as RA worsened. The direct costs increase very significantly (p < 0.0005) among the four functional classes (respectively Euro 1643.4 - 2910.2 - 4236.5 - 5696.8), likewise the indirect costs (respectively Euro 2704.9 - 9566.4 - 12183.1 - 17249.2). Moreover social costs, analysed independently from the functional classes, are significantly higher in patients with other concomitant diseases. As far as the intangible costs are concerned, for all the areas explored by the scales used, the high impact of RA on the quality of life of RA patients was markedly evident. Female gender and co-morbidity are associated with higher costs. CONCLUSIONS: In Italy, the indirect costs account for the highest cost for management of RA patients. Considering that costs increase with RA progression, the patients who show a rapid evolution of the functional damages should be identified early based on risk indicators.

[Sanitary costs of osteoarthritis] / Il consumo di risorse sanitarie per la cura dell'osteoartrosi.

Muscoloskeletal disorders are the first cause of disability and the second cause of permanent disablement in Italy. Osteoarthritis is the most frequent rheumatic disease and affects about 4 million Italians. In spite of that, data concerning social costs are lacking. On account of this lack we measured sanitary costs of 314 patients suffering from osteoarthritis. A retrospective, prevalence-based multicentric study was performed using a bottom-up approach. The study period was 12 months and referred to 1999. Eight percent of patients didn't take any drug for the treatment of osteoarthritis; NSAIDs were prescribed to 86.9% of patients, analgesics to 29.9%, chondroprotective drugs to 7.6%, and gastroprotective drugs to 36.9%. Total sanitary costs came to 455 euro / patient / year: 122 euro were spent on diagnostics, 293 euro on therapy and 40 euro on management of drug-related gastropathy. Since the costs of anti-inflammatory drugs came to 30 euro we calculated iatrogenic cost factor of 2.3. Moreover, the study supplied interesting informations about prescriptive habits, which differ in Italy from international guidelines for the medical treatment of OA, about patient management, because of hospitalization, which by itself absorbs 1/3 of resources, and about physiotherapy, which costs twice as much as pharmacological therapy. At last, data analysis gave the cue for suggestions on changing patients' management.

Validation of an Italian version of the arthritis impact measurement scales 2 (ITALIAN-AIMS2) for patients with osteoarthritis of the knee. Gonarthrosis and Quality of Life Assessment (GOQOLA) Study Group.

OBJECTIVE: To validate a translated version of the revised and expanded Arthritis Impact Measurement Scales (AIMS2) to be used by Italian patients with osteoarthritis (OA) of the knee. METHODS: The AIMS2 was translated into Italian and administered to a cohort of 178 outpatients with symptomatic OA of the knee who attended 12 participating rheumatological institutes in northern, central and southern Italy. A random sample of 71 patients were readministered the AIMS2, 7 days after the first visit, to evaluate the instrument's test-retest reliability. After 6 months, the subjects were asked to return to the institutes for a second administration of the questionnaire. RESULTS: The internal consistency reliability of each scale score, as estimated by Cronbach's alpha coefficient, was high and indicated that the components of the scale measured the same construct. The items all correlated with each other, but there was no redundancy; this indicates that each domain addressed a somewhat different aspect of functional disability. The test-retest reliability equalled or exceeded 0.80 for eight of the 12 scales. Factor analysis provided a three-factor health status model explaining 63.5% of the variance. Arthritis pain and psychological scale were loaded on the first factor, together with physical scales for mobility level and walking and bending. The upper limb function scales formed the second factor. The third factor was determined by the social dimension. These results demonstrate that the physical health status scales of the AIMS2 are valid, as shown by the significant, moderate to high correlations between the AIMS2 subscales and the majority of the clinical measures. CONCLUSION: Our data suggest that, like the original questionnaire, the translated version of AIMS2 is a reliable, consistent and valid instrument for measuring health status and physical functioning in patients with OA of the knee.