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Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthropathies, Crohn's disease, ulcerative colitis and juvenile idiopathic arthritis, comprise a group of chronic disorders characterized by an immune-mediated pathogenesis. Although at clinical presentation these diseases appear unrelated, they have been recognized to share similar pathogenic mechanisms. Data from epidemiological and genetic studies further support the concept that IMIDs are interrelated, as they can co-occur in the same patient and share a similar genetic susceptibility. The specific aetiologies of IMIDs remain unknown, but all are known to involve dysregulation of the immune system, including an over-expression of the pro-inflammatory cytokine tumour necrosis factor (TNF). The pivotal role played by TNF in the pathogenesis and pathophysiology of IMIDs has been documented by extensive preclinical and clinical investigations, and confirmed by the efficacy of anti-TNF biotechnological drugs, such as etanercept, infliximab and adalimumab, in the therapeutic management of these disorders. In this narrative review, we discuss the available data on the TNF-dependent pathogenesis of IMIDs and associations among the different disorders. Although much remains to be discovered about the pathogenesis and aetiology of IMIDs, their common inflammatory pathological features may explain why they can be successfully targeted by anti-TNF drugs. Among these, adalimumab, a fully human monoclonal antibody, has been approved for treatment ofnine distinct IMID indications and it is likely to become a valuable therapeutic tool for this complex cluster of chronic inflammatory disorders.

Tumour necrosis factor (TNF) plays an important role in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in down-regulation of abnormal and progressive inflammatory processes, resulting in rapid and sustained clinical remission, improved quality of life and prevention of target organ damage. Adalimumab is the first fully human monoclonal antibody directed against TNF. In this article, we review the role and cost effectiveness of adalimumab in the treatment of IMIDs in adults and children. The efficacy and tolerability of adalimumab has been demonstrated in patients with a wide range of inflammatory conditions, leading to regulatory approval in rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and intestinal Behçet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major tolerability issues with adalimumab are class effects, such as injection site reactions and increased risk of infection and lymphoma. As with all anti-TNF agents, adalimumab is immunogenic, although less than infliximab, and some patients receiving long-term adalimumab will develop anti-drug antibodies, causing a loss of response. Comparisons of its clinical utility and cost effectiveness have shown it to be a valid treatment choice in a wide range of patients. Recent data from Italian economic studies show the cost effectiveness of adalimumab to be below the threshold value for health care interventions for most indications. In addition, analysis of indirect costs shows that adalimumab significantly reduces social costs associated with RA, PsA, AS, Crohn's disease and psoriasis. The fact that adalimumab has the widest range of approved indications, many often presenting together in the same patient due to the common pathogenesis, may further improve the utility of adalimumab. Current clinical evidence shows adalimumab to be a valuable resource in the management of IMIDs. Further research, designed to identify patients who may benefit most from this drug, will better highlight the role and cost-effectiveness of this versatile TNF inhibitor.

The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF), has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs.

Primary CNS vasculitis (PCNSV) is an uncommon disease in which lesions are limited to the brain and spinal cord. Our objective was to evaluate the frequency, clinical features, and outcome of spinal cord involvement in PCNSV.

Retroperitoneal fibrosis encompasses a range of diseases characterised by the presence of a fibro-inflammatory tissue, which usually surrounds the abdominal aorta and the iliac arteries and extends into the retroperitoneum to envelop neighbouring structures-eg, ureters. Retroperitoneal fibrosis is generally idiopathic, but can also be secondary to the use of certain drugs, malignant diseases, infections, and surgery. Idiopathic disease was thought to result from a local inflammatory reaction to antigens in the atherosclerotic plaques of the abdominal aorta, but clinicolaboratory findings-namely, the presence of constitutional symptoms and the high concentrations of acute-phase reactants-and the frequent association of the disease with autoimmune diseases that involve other organs suggest that it might be a manifestation of a systemic autoimmune or inflammatory disease. Steroids are normally used to treat idiopathic retroperitoneal fibrosis, although other options-eg, immunosuppressants, tamoxifen-are available. The outlook is usually good, but, if not appropriately diagnosed or treated, the disease can cause severe complications, such as end-stage renal failure. Here, we review the different aspects of retroperitoneal fibrosis, focusing on idiopathic retroperitoneal fibrosis and on the differential diagnosis associated with the secondary forms.

Glucocorticosteroids are the cornerstone of treatment of giant cell arteritis. An initial dose of prednisone or its equivalent of at least 40-60mg per day as single or divided dose is usually adequate. Glucocorticosteroids may prevent, but usually do not reverse, visual loss. A treatment course of 1-2 years is often required. Some patients, however, have a more chronic-relapsing course and may require low doses of glucocorticosteroids for several years. Glucocorticosteroid-related adverse events are common. In studies on immunosuppressant agents, methotrexate has been used as a glucocorticosteroid-sparing drug with conflicting results. This drug may, however, be given to patients who need high doses of glucocorticosteroids to control active disease and who have serious side effects. A recent pilot study found that infliximab was efficacious in patients with glucocorticosteroid-resistant giant cell arteritis. However, randomized controlled trials are required to define the role of anti-tumor necrosis factor-@a agents in the treatment of giant cell arteritis. Finally, low-dose aspirin has been shown in a recent retrospective study to decrease the rate of cranial ischemic complications secondary to giant cell arteritis. It is conceivable that the definition of different patterns of inflammation in giant cell arteritis in the future might facilitate the design of differentiated therapeutic approaches.

Takayasu's arteritis (TA) is a rare vasculitis. The Italian Takayasu's Arteritis study group was established with the aim to describe a large cohort of patients.Data were collected by means of an ad hoc form. Demographic information, clinical history, vascular findings, treatment, risk factors, and comorbidities were analyzed.Data of 104 patients were collected. The median delay in diagnosis was 15.5 months (range 0–325 months). Age at onset <15 years was associated with a higher probability, whereas elevated erythrocyte sedimentation rate with a lower probability, of a delay in diagnosis. The majority of patients experienced nonspecific signs and symptoms indicative of an inflammatory disease in the early phase. Among vascular involvement, stenosis was the most frequent lesion, being present in 93% of patients, followed by occlusion (57%), dilatation (16%), and aneurysm (7%). Glucocorticoids were the mainstay of treatment in our series; however, treatment with cytotoxic agents was required in about half of the patients. Fifty‐two patients underwent at least 1 surgical procedure. The main indications for intervention were renal vascular hypertension, cerebral hypoperfusion, and limb claudication.As with many rare diseases, delay in diagnosis is an important issue for patients with TA. The increasing occurrence of vascular lesions along with the disease progression put to question the long‐term effectiveness of contemporary treatment. These data may be helpful in increasing physicians' awareness to prevent diagnosis delay, update guidelines, and plan future research projects.

This paper aims to evaluate adrenal gland hormone levels in patients with polymyalgia rheumatica (PMR) during glucocorticoid (GC) therapy. A lower than expected basal production of cortisol was found in active and glucocorticoid-untreated PMR patients, particularly females. The abrupt onset of PMR with clinical features similar to those of the steroid-withdrawal syndrome or adrenal insufficiency, as well as the clinical response to GC therapy in elderly people already age-disposed to an inadequate adrenal and anti-inflammatory response, might represent the most significant pathophysiological basis of the disease.

OBJECTIVE: To compare the efficacy and tolerability of cyclosporine (CSA) with that of symptomatic therapy (ST) alone and sulfasalazine (SSZ) in the treatment of psoriatic arthritis (PsA). METHODS: Twelve rheumatology centers recruited 99 patients with active PsA in a 24 week, prospective, randomized, open, controlled study. The patients were treated with CSA (3 mg/kg/day) or SSZ (2,000 mg/day) plus ST, or ST alone (nonsteroidal antiinflammatory drugs, analgesics, and/or prednisone < or = 5 mg/day). The primary endpoint was the 6 month change in pain. Analyses were on the basis of the intention-to-treat principle. RESULTS: In comparison with both SSZ and ST, there was a statistically significant difference in favor of CSA in terms of the mean changes in the pain score (p < 0.05), which was considered the primary response variable. A significant decrease in favor of CSA versus ST alone was also observed for swollen joint count (p = 0.05), tender joint count (p = 0.01), joint/pain tenderness score (p = 0.002), patient and physician global assessment by at least one point (p = 0.04 and 0.01, respectively), total Arthritis Impact Measurement Scale score (p = 0.002), and spondylitis functional index (p = 0.002). There was a statistically significant difference in the ACR 50% and ACR 70% response rates between the CSA and ST groups (p = 0.02, 0.05). Comparing the SSZ and ST alone groups, only the spondylitis functional index decreased significantly in the SSZ treated patients (p = 0.03). The Psoriasis Area and Severity Index was significantly lower in the CSA than in the ST and SSZ groups (p = 0.0001 and 0.01, respectively). Decrease in erythrocyte sedimentation rate was significant only in the SSZ versus the ST group (p = 0.02), whereas reduction in C-reactive protein was significant in the CSA treated patients compared with the ST group (p = 0.006). The most common adverse event in the CSA group was mild, reversible kidney dysfunction. CONCLUSION: The results of this open trial confirm that CSA is well tolerated by patients with PsA and suggest that it is more efficacious than ST or SSZ.

OBJECTIVE: To evaluate the distribution of the MHC class I chain related gene A transmembrane (MICA-TM) alleles in Italian patients with Behçet's disease (BD), and to investigate the relative contribution of MICA alleles and HLA-B51 in the susceptibility and specific clinical features of BD. METHODS: A total of 69 consecutive Italian patients who satisfied the International Study Group criteria for BD were followed at rheumatology, ophthalmology, and neurology units during a 3 year period (1997-99). We selected 130 healthy subjects from the same geographic areas as controls. All patients and controls were examined for MICA microsatellite polymorphisms using polymerase chain reaction. Serological HLA class B51 typing was performed by a standard microlymphocytotoxicity technique. RESULTS: A strong association with HLA-B51 was observed in patients with BD (OR 5.7, 95% CI 2.8-11.3). The MICA-TM allele A6, in linkage disequilibrium with HLA-B51, was only slightly increased in patients compared to controls (60.9% vs 50.8%; p = NS). No significant associations between HLA-B51 or MICA-TM alleles and clinical subgroups, particularly central nervous system or eye involvement, were found. CONCLUSION: HLA-B51 is the most important susceptibility gene in BD. Association with MICA-A6, when it exists, is secondary to the strong linkage disequilibrium with HLA-B51.

OBJECTIVE: Intercellular adhesion molecule 1 (ICAM-1) is strongly expressed in vascular endothelial cells and perivascular inflammatory infiltrates in immunopathologic studies of Behçet's disease (BD) lesions. ICAM-1 genes may contribute to the inflammatory events responsible for the vessel damage in BD. We examined potential associations of ICAM-1 gene polymorphisms with BD susceptibility. METHODS: Case patients were 74 consecutive Italian patients with BD who were followed at the Bologna, Ferrara, Milano, Potenza, Prato, Reggio Emilia, and Trento rheumatology, ophthalmology, and neurology units over a 3 year period (1997-99) who satisfied the International Study Group criteria for BD; 228 healthy Italian blood donors from the same geographic areas were selected as control groups. All BD patients and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for ICAM-1 polymorphisms at codon 241 (exon 4) and codon 469 (exon 6). RESULTS: The frequency of R241 was significantly higher in BD patients than in controls (20.3% vs 5.7%; p = 0.001, pcorr = 0.002, OR 4.2, 95% CI 1.9-9.3). The distribution of E/K 469 genotype was similar in patients and controls. Comparing patients with different clinical features, we found only a trend to higher frequency of R241 in patients with articular manifestations (21.4% vs 12.5%; p = 0.08). CONCLUSION: Our findings show that G/R 241 polymorphism of ICAM-1 is associated with BD susceptibility.

OBJECTIVE: Magnetic resonance imaging (MRI) showed that subacromial/subdeltoid bursitis is the most frequent shoulder lesion in polymyalgia rheumatica (PMR). We evaluated whether shoulder ultrasonography (US) was as effective as MRI in the detection of this lesion and assessed the sensitivity and specificity of bilateral subacromial/subdeltoid bursitis in the diagnosis of PMR. METHODS: A case-control study of 57 consecutive case patients with untreated PMR and 114 controls seen over a 6 month period in 3 secondary referral rheumatology centers. Control patients consisted of the next 2 consecutive patients with bilateral shoulder aching and stiffness observed after the case patient. In all case and control patients the glenohumeral joint space, bursae, and long head biceps tendon were assessed by bilateral shoulder US. The first 24 case patients were also examined by bilateral shoulder MRI. RESULTS: US showed subacromial/subdeltoid bursitis in 55/57 (96%) patients with PMR and in 25/114 (22%) controls (p < 0.001). The lesion was bilateral in 53/55 (96%) case patients and in 1/25 (4%) controls (p < 0.001). The frequency of glenohumeral joint synovitis and biceps tenosynovitis did not differ significantly between case patients and controls. In 100% of case patients MRI showed subacromial/subdeltoid bursitis confirming US findings. The sonographic evidence of bilateral bursitis had a sensitivity of 92.9%, specificity of 99. 1%, and positive predictive value of 98. 1% for the diagnosis of PMR. CONCLUSION: US and MRI were equally effective in confirming bilateral subacromial and subdeltoid bursitis in PMR. This finding, in view of its high sensitivity and specificity, could be used as a new diagnostic criterion for PMR.

Abstract: The aim of the study was to evaluate the frequency of extra-articular manifestations (EAMs) of rheumatoid arthritis (RA) in a series of patients from nine Italian rheumatology clinics. A total of 587 patients underwent direct questioning, complete physical evaluation, and review of medical records and laboratory data. The relationships between EAMs and the eosinophilic count, IgM rheumatoid factor (RF), and antinuclear antibodies (ANA) were studied. EAMs were present in 240/587 (40.9%) patients. The most common features were sicca syndrome (17.5%) and rheumatoid nodules (16.7%). EAMs were significantly more frequent in male patients (OR=1.68), patients with ANA positivity (OR=2.82), high anatomical class (OR=2.3), and rheumatoid factor seropositivity (OR=2.22). EAMs were more common in patients from southern Italy than in those from northern Italy (P < 0.001). EAMs seem to be rarer in Italy than in the Anglo-Saxon populations of northern Europe and the USA. Differences in prevalence of EAMs can exist even within the same country.

Summary Fifty-two patients with psoriatic arthritis (PA), treated with auranofin (AF), were entered into a one year prospective, open study. The total group showed a significant increase in frequency of HLA antigens A1 and B38, and a reduction of B5 when compared to healthy controls. There was a remission or an important improvement of disease in the 51 % of 45 patients who completed the study. The rate of withdrawal due to side effects was low (8.8%) and the toxicity was mild in nature (diarrhoea and mucocutaneous rash). We prospectively sought predictors of response using HLA antigens, and clinical and laboratory parameters at the beginning of therapy. The only 3 factors found to be related to outcome were duration of psoriasis, physician and patient assessment of disease activity. No laboratory data or HLA specificities could be associated with substantial response to AF therapy.

Objective. To investigate the effects of desferrioxamine (DFO) infusion on chronic disease anemia (CDA) of rheumatoid arthritis (RA) by evaluating interleukin-6 (IL-6) and erythropoietin (EPO) production.Patients and methods. Five patients with RA and CDA (group I) were treated with DFO, 500 mg daily, through a continuous 10-h subcutaneous infusion 5 days a week for 4 weeks. One month after withdrawal, DFO was resumed in all five group I patients (group II) with an increase to 1 g daily following the previous treatment schedule. Clinical and laboratory parameters were evaluated weekly during the two study periods. Serum EPO was measured by radioimmunoassay. IL-6 was detected by the enzyme-linked immunoabsorbent assay method.Results. No significant variations in hematological parameters, IL-6 or EPO levels were observed in group I patients. After 1 week of DFO 1 g daily, reticulocyte counts and EPO improved significantly. Hemoglobin and hematocrit rose significantly after 3 weeks of 1 g daily DFO therapy. Four weeks after DFO withdrawal, EPO, reticulocyte counts, hemoglobin and hematocrit returned to baseline levels. A significant improvement in the clinical parameters of disease activity was observed, particularly in group II patients.Conclusion. DFO improves CDA in RA patients. The beneficial effects on erythropoiesis seem to be related to improved EPO responsiveness to the anemia.

Summary The patient, a 55-year-old man with neuro-Behçet, developed superior vena caval occlusion. Antibodies to cardiolipin were detected in high titres in his serum and a decreased fibrinolysis was also found. It is suggested that anticardiolipin antibodies, perhaps decreasing fibrinolysis, may play an important pathogenic role in some patients with Behçet's disease.

The aim of the study was to evaluate the relationship between the presence of the 'rheumatoid epitope' defined by a sequence motif in the HLA-DRB1 alleles, rheumatoid factor and disease severity in Northern Italian patients with rheumatoid arthritis (RA). Twenty-nine DR4-positive and 47 DR4-negative RA patients were studied. Each DR4-positive patient was matched with two DR4-negative controls of similar disease duration and sex. HLA-DRB1 alleles were determined in the 86 patients and 351 controls from the same geographical area. The patients were retrospectively evaluated for extra-articular features (EAF) and radiographic damage. The rheumatoid epitope was expressed in 45% of patients. No significant differences in the presence of rheumatoid factor, EAF and articular damage were observed between patients with no, one or two doses of epitope. However, the patients encoding the epitope by an HLA-DR4 allele had a higher number of eroded joints and a higher Larsen score compared to those without the epitope. No differences were present between patients expressing HLA-DRB1*-01 alleles and those lacking the rheumatoid epitope. Even in the absence of expression of the rheumatoid epitope, seropositive patients had more EAF and more erosive disease compared to those who were seronegative. Even if most Northern Italian RA patients do not express the rheumatoid epitope, the radiological severity of disease is associated with HLA-DRB1*04 alleles.Key words: Rheumatoid arthritis, Severity, HLA-DRB1 alleles, Rheumatoid factor.

Aims of the study to evaluate the radiologically detected progression of joint damage in patients with psoriatic arthritis (PA) treated with cyclosporin-A (CsA) and to look for clinical and/or immunological parameters that might predict outcome. Twenty-four out-patients suffering from active PA entered a 2-year open prospective study on low-dose CsA (starting dose 3 mg/kg/day). Fifteen patients completed the study. Plain radiographs of hands and feet at study entry and at the end of follow-up were compared for the number of eroded joints. Serum-soluble IL-2 receptor (sIL-2R) levels were available in 13/15 patients before CsA therapy, after 6 months and after 2 years. The mean number of eroded joints per patient increased significantly during the study period (P=0.017). Nine patients had less than two new eroded joints (responders) while the remaining six patients had five or more new eroded joints (non-responders). Serum sIL-2R levels were in the normal range after 6 months and 2 years of CsA treatment in all the responder patients and were above the 95th percentile of the control population in the six non-responders. We did not find any other demographical, clinical, radiological or laboratory parameter predictive of outcome in conclusion. (1) CsA seems to be able to control the 2-year progression of the radiologically measured damage in peripheral joints in 60% of PA patients. (2) A normal serum sIL-2R level after 6 months of therapy seems to have a prognostic value for a good outcome in PA patients treated with CsA.

The aim of the study was to evaluate the relationship between the presence of the 'rheumatoid epitope' defined by a sequence motif in the HLA-DRB1 alleles, rheumatoid factor and disease severity in Northern Italian patients with rheumatoid arthritis (RA). Twenty-nine DR4-positive and 47 DR4-negative RA patients were studied. Each DR4-positive patient was matched with two DR4-negative controls of similar disease duration and sex. HLA-DRB1 alleles were determined in the 86 patients and 351 controls from the same geographical area. The patients were retrospectively evaluated for extra-articular features (EAF) and radiographic damage. The rheumatoid epitope was expressed in 45% of patients. No significant differences in the presence of rheumatoid factor, EAF and articular damage were observed between patients with no, one or two doses of epitope. However, the patients encoding the epitope by an HLA-DR4 allele had a higher number of eroded joints and a higher Larsen score compared to those without the epitope. No differences were present between patients expressing HLA-DRB1*-01 alleles and those lacking the rheumatoid epitope. Even in the absence of expression of the rheumatoid epitope, seropositive patients had more EAF and more erosive disease compared to those who were seronegative. Even if most Northern Italian RA patients do not express the rheumatoid epitope, the radiological severity of disease is associated with HLA-DRB1*04 alleles.

The original descriptions of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in the medical literature date back to 1888 and 1890, respectively. Classification criteria for PMR and GCA are not standardized since most authors used subjective criteria based on their personal experience. Only one study has evaluated criteria for PMR and has found seven variables with high discriminant value. Criteria for GCA are less varied because a positive biopsy of the temporal artery is diagnostic. However, combinations of different clinical and laboratory features have been used for diagnosis when biopsy is negative or missing. Assessment of PMR/GCA is based on the serial determination of markers of acute phase such as ESR, CRP, or plasma viscosity. However, their value in predicting recurrence of the diseases is poor. New immunological factors including soluble interleukin-2 receptors, interleukin-6, serum soluble CD8, and serum soluble intercellular adhesion molecule-1 are presently under investigation.

Summary A case of polyarteritis nodosa identified by the American College of Rheumatology (ACR) 1990 criteria in a 44-year-old HIV-infected man is described. The search for cytomegalovirus, HBV and B19 parvovirus infections was negative.In situ hybridization did not reveal proviral HIV-1 DNA in a skin sample. A zidovudine-associated vasculitis was excluded. Corticosteroid therapy resolved vasculitis manifestations and was well tolerated without opportunistic infections during the 10-month follow-up period. An indirect pathogenetic role of HIV as a possible cause of vascular damage cannot be excluded in our patient.

Musculoskeletal symptoms may predominate and may be the presenting feature of hypothyroidism. Hochberg et al. (1) reported on 2 hypothyroid patients with a muscular syndrome presenting clinical and laboratory features indistinguishable from polymyositis. We also have observed 2 patients in whom muscle weakness and tenderness combined with marked elevation of serum muscle enzymes led us to a misdiagnosis of polymyositis.

Background: PMR patients have high systemic levels of IL-6 which correlate with prognosis. IL-6 mediates its activity through two membrane proteins: IL-6R and gp 130 (signal transducing element). Soluble complexes of IL-6R and IL-6, are able to associate to membrane-bound gp130 and thus they mediate intracellular signalling in IL-6R negative cells. Biological activity of sIL-6R/IL-6 complexes can be blocked by soluble gp130. We investigated the modulation of systemic levels of sIL-6R and gp130 in patients both in active disease and during corticosteroid treatment and the ability of peripheral blood mononuclear cells (PBMC) to contribute to circulating levels of these molecules.Methods: We analyzed sIL-6R and gp 130 serum levels in 44 PMR patients at disease onset and after 1, 3, 6, 12, 24 months of follow-up and in 46 age-matched normal controls (NC). Furthermore we analyzed the ability of PBMC isolated from 13 untreated PMR patients and 13 healthy subjects to release sIL-6R and gp130 in basal condition and upon stimulation with lipopolysaccharide (LPS) and anti-CD3. Serum and supernatant levels were determined by ELISA.Results: No difference in sIL-6R and gp 130 serum levels were noted between PMR and NC cases, either at disease onset or during follow-up. On the contrary, sIL-6R and gp130 production by PBMC obtained from untreated PMR patients was significantly higher compared to NC either in basal condition or after stimulation with LPS and anti-CD3.Conclusions: At variance with other inflammatory diseases, we showed neither increase of sIL-6R serum levels nor decrease gp130 levels. Increased production by PMR PBMC does not modify normal serum levels.

Background: Although GCA is responsive to glucocorticoids (GCS), therapy causes significant toxicity and often fails to induce sustained remission.Purpose: Assess safety and efficacy of infliximab (IFX) in patients (pts) with new onset GCA in a randomized, double-blind, placebo-controlled, multi-center, Phase II study.Methods:Eligibility: diagnosis of GCA (ACR criteria); GCA of ≤4 weeks (wks) duration; resolution of GCA features and normal ESR following treatment with 40–60 mg prednisone or prednisolone/day; remission for 1 wk prior to randomization. Exclusions: absence of infection, malignancies within 5 years, congestive heart failure and advanced disease of critical organs. Treatment randomization: 1:2 ratio, to receive infusions of placebo or IFX 5 mg/kg, respectively, at wks 0, 2, 6, 14, 22, 30, 38, 46. All pts received GCS on a specified tapering schedule with starting dose between 40–60 mg/day. Visits: every 4 wks, through 54 wks; interim analyses at wk 22. Primary endpoints: proportion of relapse-free patients through wk 22 and safety (frequency and types of adverse events). Relapse definition: rise in ESR, normal to ≥40 mm; and one of following (i) 1 or more specified features of GCA; and (ii) any other features of GCA not attributable to any other cause and a concomitant increase in dose of GCS. Secondary endpoints included: (i) proportion of relapse-free patients at week 54; (ii) time to 1st relapse; and (iii) cumulative dose of GCS.Results: 44 pts were randomized (placebo, n = 16, IFX, n = 28) at 22 centers in 5 countries. Mean age in both groups (gps) was 71.0 years (range: 50–93). Baseline features between gps were comparable except for gender (placebo 31.3% males vs. IFX 14.3% males); fever (placebo 50.0% vs. IFX 17.9%) and visual impairment (placebo 31.3% vs. IFX 7.1%). More IFX-treated pts had positive temporal artery biopsies (66.7 placebo vs. IFX 92.3%). Efficacy was evaluated using cumulative data from 22 wks follow up. There were no differences between gps in regard to: (1) proportion of pts remaining relapse-free (50% placebo vs. 43% IFX, p = 0.651), (2) cumulative doses of GCS therapy (placebo mean±SD = 3117±971 mg vs. IFX = 3051±770 mg, p = NS) and (3) among pts who had 1st relapse, days to 1st relapse (placebo median = 84.5, IFX median = 96.5, p = NS). There was 1 case of heart failure in an IFX-treated pt. Infections were infrequent and limited to upper respiratory tract (12.5% placebo vs. 14.3% IFX).Conclusions: In this elderly population of pts with newly diagnosed GCA, IFX 5 mg/kg every 8 weeks, was well-tolerated, but during 22 weeks of treatment did not reduce number of 1st relapses or cumulative GCS dosage.

Introduction: We have recently demonstrated that combination therapy with prednisone and methotrexate (MTX) is effective as steroid-sparing treatment for patients with newly diagnosed polymyalgia rheumatica (PMR) [1]. This schedule reduces the incidence of flare-ups and the amount of prednisone required to maintain remission. However, no substantial reduction was found in the incidence of steroid-related side effects in the MTX-treated patients, despite the lower cumulative dose of prednisone they received. Possible explanations are the narrow difference in the cumulative dose of prednisone between groups, and the low incidence of side effects in this relatively “healthy” group of PMR patients, a common problem of controlled trials. Another possibility is the short follow-up. To test this last hypothesis, we decided to review the charts of the participating patients and to visit them again after a mean period of 5 years after completion of the original study.Patients and methods: Four of the original five rheumatologic tertiary referral centres, covering 61 of the original 72 (84.7%) patients, agreed to participate in the study. Patients were contacted by phone and asked to visit the clinic. If the patient was dead, a close relative was interviewed and information was collected on his/her previous health conditions and cause of death through a standardized questionnaire.Results: Data were obtained from 47/61 (77%) of the original patients. Five patients (10.6%) had died because of cerebrovascular accident, myocardial infarction, congestive heart failure (2 patients), or unknown cause. Two of the 23 MTX-treated patients (8.7%) had died in comparison with 3/24 (12.5%) controls. Exacerbations and relapses of PMR were seen in 4/23 (17.4%) MTX-treated patients in comparison with 10/24 (41.7%) controls (p = 0.11 by Fisher's exact test). Five out of 23 (21.7%) MTX-treated patients were still on steroids 5 years after completion of the study in comparison with 11/24 (45.8%) controls (p = 0.12). Girdle pain and stiffness, as well as results of the HAQ were not different in the two subgroups. Pain intensity, general health and physician's opinion on the patient's conditions by visual analogue scale tended to be better in MTX-treated patients than in controls, although not significantly so (20.2±21.1 mm vs. 17.2±22.7 mm, 17.3±19.7 mm vs. 13.7± 21.1 mm, and 13.2±18.8 mm vs. 6.9±8.6 mm, respectively). ESR (15.5 mm/h vs. 25.4 mm/h, p = 013) and CRP (2.7 mg/L vs. 11.3 mg/L, p = 0.009) were lower in MTX-treated patients.Potential side effects of steroid treatment were relatively rare. No differences were observed in their incidence, with a mean of 1.9 side effects for MTX-treated patients and 2.6 for controls. The analysis of single steroid-related side effects gave similar results.Conclusions: In this long-term evaluation of the effect of MTX supplementation for PMR patients, there was a tendency toward less residual disease activity over 5 years in MTX-treated patients. However, complications of steroid treatment were rare in both groups without a significant difference between them. To assess whether MTX-supplementation therapy could spare some side-effects of steroids, a prospective evaluation of unselected patients is probably more appropriate.

Objective: Since Takayasu arteritis (TA) may present in a different manner in different countries, an Italian collaborative study group was established (ITAKA – Italian Takayasu Arteritis Study Group) with the purpose to identify a significant number of Italian patients with TA and to evaluate its clinical features, angiographic findings, and treatment.Methods: We identified TA patients using the administrative data of all hospital discharges occurred in Italy between 1995 and 1997 and the Italian TA registry. The diagnosis of TA was made according to the 1990 ACR criteria. Only patients who had been followed during the previous 12 months were included in the study. 104 patients with TA were studied. Data on clinical features, angiographic and laboratory findings, pregnancies, medical and surgical treatment were recorded.Results: 99% of our patients were Caucasians and females (87.5%) were most frequently affected. The median age at disease onset was 29.2 years. The age <15 years and an erythrocyte sedimentation rate (ESR) <30 mm/h were associated to a higher probability of a delay in diagnosis ≥2 years. The most common clinical finding at diagnosis was a bruit (90%). 71% of the patients had at disease onset constitutional/musculoskeletal symptoms.61 patients had a full aortography: stenosis was the most frequent lesion (93%), followed by occlusion (57%), dilatation (16%) and aneurysm (7%). The number of lesions per patient increased with disease duration. Claudication of the limbs, Raynaud's phenomenon and distal cutaneous hypothermia were more frequent in patients with lesions of subclavian and/or iliac arteries (78.4% vs. 40.0%; p = 0.02). Headache, dizziness, syncopal attacks, convulsions, TIA and stroke were more frequent in patients with lesions of vertebral and/or carotid arteries (62.8% vs. 22.2%; p = 0.005). Hypertension was more frequent in patients with renal artery stenosis (92.0% vs. 30.6%; p<0.0001). The yearly incidence of pregnancies decreased from 8.2 every 100 fertile women before the onset of TA to 2.8 after the onset of the disease. We registered a trend towards an increasing in the percentage of spontaneous abortion after the onset (11% vs. 21%, p = 0.6).Glucocorticoids were the most frequently used drugs, being prescribed to 86% of patients, while cytotoxic agents were prescribed to 54%. 52 patients underwent to at least one surgical procedure: percutaneous transluminal angioplasty (PTA) was performed in 54% of the patients, by-pass in 42%, PTA with stent in 21%, aneurysm repair and aortic valve replacement in 8% each.Conclusion: The main socio-demographic and clinical characteristics of our large series of Italian patients with TA are similar to those described in a Japanese nationwide survey. These results suggest that TA could not be so different between Eastern and Western countries, as it has been often claimed.

The aim of this study was to evaluate CD8 lymphocyte subsets in active polymyalgia rhcumatica (PMR), to determine whether low percentages of CD8+ cells could be used to differentiate PMR from elderly-onset (EORA) and adult rheumatoid arthritis (RA), and to investigate the effects of prednisone on CD8 lymphocyte subsets. A significant reduction of percentages and absolute numbers of CD8bright+ cells was observed in patients with active PMR. Both CD8bright+ , CD57− and CD8bright+, CD57+ subsets were significantly reduced. Reduced percentages of CD8+ cells were observed in 55% of patients with active PMR/giant cell arteritis (GCA), in 23% with EORA and in 44% with adult RA. Prednisone therapy in PMR patients, after only 1 week, increased the lymphocyte count and the absolute numbers of lymphocyte subsets significantly. However, the percentages of CD8bright+ cells remained persistently low for the 2 yr study period in 80% of the patients with low pre-treatment levels. Our results demonstrate that CD8 cell percentage is a poor epidemiological discriminator for PMR diagnosis. Notwithstanding the rise in absolute numbers of CD8 cell subsets induced by prednisone, the persistently low percentages of CD8+ cells in a group of PMR patients indicate an abnormality connected with the disease.