Immunoglobulin A antibodies to oxidized collagen type II as a potential biomarker for the stratification of spondyloarthritis from rheumatoid arthritis.

OBJECTIVES: The discovery of diseased tissue-specific neoantigens offers the opportunity to develop important disease tissue-specific biomarkers that can help in the prediction, diagnosis, and stratification of diseases. This opportunity is specifically significant for autoimmune diseases where diagnostic biomarkers are not available. Inflammatory autoimmune diseases are commonly associated with local generation of large amounts of reactive oxidants. We have previously identified oxidative post-translationally modified (oxPTM) tissue-specific neoantigens in rheumatoid arthritis (RA) and type 1 diabetes that elicit an immune response. In the current study, we studied the presence and clinical significance of antibodies to oxPTM collagen type II (CII) in patients with spondyloarthritis (SpA). METHOD: Levels of antibodies specific to native CII and oxPTM-CII were assessed by enzyme-linked immunosorbent assay. RESULTS: Immunoglobulin G (IgG) binding to oxPTM-CII was observed in 52%, 83%, and 28% of serum samples from patients with axial spondyloarthritis (axSpA), RA, and psoriatic arthritis (PsA), respectively. Importantly, while strong IgA anti-oxPTM-CII responses were detected in axSpA and PsA patients, with 47% and 84% respective binders, no IgA anti-oxPTM-CII was detected in RA patients. IgA anti-oxPTM-CII reactivity in axSpA patients treated with biologics was higher and more frequent, with 85% binders compared to 9% binders in patients treated with synthetic disease-modifying anti-rheumatic drugs. CONCLUSION: Our data imply that SpA and PsA are associated with the presence of antibodies to oxPTM-CII, suggesting that there may be a humoral component that may distinguish patients with SpA from RA. Our approach could be adapted to other diseases, particularly to inflammatory autoimmune diseases.

Combining immunofluorescence with immunoblot assay improves the specificity of autoantibody testing for myositis.

OBJECTIVE: Immunoblot (IB) methods are widely used to detect myositis-specific autoantibodies (MSAs); however, false-positive results are common. In this study, we aimed to determine whether associating the anti-nuclear antibody (ANA) IIF pattern may help to improve the specificity of MSA detection by IB in patients with idiopathic inflammatory myositis (IIM). METHODS: Serum samples from 104 patients presenting with muscle weakness/myalgia and positive to at least one MSA by IB (MYOS12 Diver and MIOS7 Diver, D-tek) were tested for ANAs on HEp-2000 cells (Immuno Concepts). The chi-square test was used to analyse the concordance of the MSA result and its corresponding pattern by ANA testing between patients with and without IIM. RESULTS: Eighty-three of the 104 patients had a diagnosis of definite IIM, while in 21 cases, patients were affected by other autoimmune diseases or various non-systemic diseases. Forty nine of 83 (59%) patients in the IIM group and 4/21 (19%) in the non-IIM group showed a concordance between ANA pattern and MSAs by IB (P < 0.001). MSA monopositivity was significantly associated with IIM (91.6%) compared with 61.9% in the non-IIM group (P = 0.0005). CONCLUSIONS: Considering both the MSA result and its corresponding pattern by ANA testing may help to improve the specificity of MSA detection by IB and to confirm the diagnosis of MSA-associated IIM. The monopositivity of MSAs is an important additional tool to validate IB results.

Autoantibody profile and clinical patterns in 619 Italian patients with cutaneous lupus erythematosus.

BACKGROUND: Anti-nuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-dsDNA antibodies are often associated with cutaneous lupus erythematosus (CLE), with variable frequency depending on skin subtype. However, specific data based on large case-series on the pathogenetic, diagnostic and prognostic meaning of such autoantibodies are still lacking. OBJECTIVE: To characterize the correlations between CLE subtypes as well as LE-non-specific skin lesions and their autoantibody pattern. METHODS: Epidemiological, clinical and immunopathological data of 619 Italian patients with CLE and LE-non-specific skin lesions were analysed. Differences in age, sex, clinical features and autoantibody profile were evaluated in each LE subgroup. RESULTS: Anti-nuclear antibodies (P < 0.0001), anti-dsDNA (P < 0.0001), ENA (P = 0.001), anti-Sm (P = 0.001), anti-RNP (P = 0.004) and anti-histone (P = 0.005) antibodies were associated with SLE. A strong association between ANA (P < 0.0001) and anti-dsDNA (P < 0.0001) and female gender was also found: positive ANA and positive anti-dsDNA had a higher prevalence among females. Chronic CLE resulted to be negatively associated with ENA (OR = 0.51, P < 0.0001), anti-Ro/SSA (OR = 0.49, P < 0.0001) and anti-dsDNA (OR = 0.37, P < 0.0001). Intermittent CLE resulted to be negatively associated with ENA (OR = 0.50, P = 0.007) and ANA (OR = 0.61, P = 0.025). Subacute CLE resulted to be associated with ENA (OR = 5.19, P < 0.0001), anti-Ro/SSA (OR = 3.83, P < 0.0001), anti-Smith (OR = 2.95, P = 0.004) and anti-RNP (OR = 3.18, P = 0.007). Acute CLE resulted to be strongly associated with anti-dsDNA (OR = 6.0, P < 0.0001) and ANA (OR = 18.1, P < 0.0001). LE-non-specific skin lesions resulted to be significantly associated with systemic involvement. Livedo reticularis was significantly associated with ENA (P = 0.007) and anti-Ro/SSA (P = 0.036). Palpable purpura and periungual telangiectasia were significantly associated with ANA. CONCLUSION: According to our findings, some well-known associations between CLE subtypes and autoantibody profile were confirmed; moreover, specific association between autoantibodies and LE-non-specific skin lesions was highlighted. A strict association between anti-ENA and anti-Ro/SSA antibodies and livedo reticularis, ANA and palpable purpura, and ANA and periungual telangiectasia was evidenced.

The impact of biological treatments on the anti-dsDNA and anti-nucleosome tests.

Background Anti-double stranded DNA antibodies are a very heterogeneous group of antibodies, quite specific for systemic lupus erythematosus. Newer technologies, such as addressable laser bead immunoassays (ALBIA), show great potential as a diagnostic application. The production of anti-double stranded DNA antibodies is often encountered in inflammatory arthritis; however, literature reports that the actual onset of drug induced lupus in patients treated with biological drugs is a rare event. False positive results for anti-double stranded DNA and anti-nucleosome antibodies detected in patients with inflammatory arthritis treated with different biologics prompted the investigation of full autoantibody profiles to evaluate each biomarker's diagnostic performance in systemic lupus erythematosus. The aim of the study was to compare the diagnostic performance of anti-double stranded DNA antibody and anti-nucleosome antibody methods and to evaluate the value of simultaneously measuring anti-double stranded DNA and anti-nucleosome antibodies, along with other anti-nuclear antibody analytes, as biomarkers for systemic lupus erythematosus, using a more appropriate control cohort including inflammatory arthritis patients with a non-clinical drug induced lupus. Methods Anti-double stranded DNA and anti-nucleosome antibody levels were evaluated in 247 patient samples: 70 systemic lupus erythematosus, 177 disease controls (including 97 inflammatory arthritis during treatment with different biologics) using the Bio-Rad BioPlex® 2200. Results Anti-nucleosome antibodies demonstrated greater clinical sensitivity and specificity than anti-double stranded DNA antibodies. At the manufacturers' cut-off range, considering the two markers as a single or combined test, the "anti-double stranded DNA test or anti-nucleosome antibodies" was the most sensitive combination (0.400) with the best negative likelihood ratio (0.62) and negative predictive value (0.803). Conclusion Anti-nucleosome antibodies are a more sensitive and specific biomarker of systemic lupus erythematosus than anti-double stranded DNA antibodies. Anti-nucleosome antibodies and anti-double stranded DNA antibodies are independent and complementary markers of systemic lupus erythematosus diagnosis and, therefore, are strongly suggested as combined tests (positive predictive value = 0.938). Moreover, the combined use of the two tests may help to overcome the decreased specificity percentage of the anti-double stranded DNA test, when considering an inflammatory arthritis cohort under biological therapies. The ALBIA method for anti-nuclear specificity detection allows a full autoantibody assessment, resulting in a much higher clinical specificity for systemic lupus erythematosus in the presence of ≥3 positive markers and significantly more positive likelihood ratio when ≥2 positive markers are present.

Jaccoud's arthropathy, an unusual manifestation of idiopathic retroperitoneal fibrosis: rapid improvement of symptoms after tocilizumab treatment.

Jaccoud's arthropathy (JA) is a chronic, non erosive, rheumatoid-like deformity associated with rheumatic fever (RF) and systemic lupus erythematosus and with other diseases such as psoriatic arthritis, connective tissue diseases, hypocomplementemic urticarial vasculitis, infections, sarcoidosis and neoplasia. We described a case of JA in a patient with cutaneous psoriasis but with a particular disease evolution associated with idiopathic retropritoneal fibrosis (IRF), evaluated with computed tomography, magnetic resonance and 18F-FDG PET/ CT. The patient, following failure with steroids, methotrexate and etanercept, was treated with tocilizumab (8 mg/kg) once every 4 weeks for 6 months. A rapid improvement of symptoms and disappearance of 18F-FDG uptake was shown. We describe a review of literature of rheumatic manifestations of IRF and the possible role of interleukin-6 in the pathway of JA and IRF.

The role of klotho in systemic sclerosis.

The aim was to evaluate the role of klotho in the pathogenesis of systemic sclerosis (SSc), through the measurement of its serum concentration in SSc patients compared to healthy controls, and to assess the association with cutaneous and visceral involvement. Blood samples obtained from both SSc patients and healthy controls were analysed by an ELISA assay for the detection of human klotho. SSc patients were globally evaluated for disease activity and assessed through the modified Rodnan's Skin Score, Medsger's scale, pulmonary function tests, 2D-echocardiography, nailfold capillaroscopy and laboratory tests. Our cohort consisted of 69 SSc patients (61 females, mean age 64.5±12.5 years, median disease duration 9.0 (IQR 8) years) and 77 healthy controls (28 females, mean age 49.7±10.2 years). In the group of SSc patients, 19 (27.5%) suffered from a diffuse form of SSc. All patients were receiving IV prostanoids, and some of them were concomitantly treated with immunosuppressive drugs (prednisone, hydroxychloroquine, mofetil mycophenolate, methotrexate, cyclosporin A and azathioprine). The median serum concentration of klotho was significantly lower in patients compared to controls (0.23 ng/mL vs 0.60 ng/mL; p<0.001). However, Spearman's test showed no significant association between klotho serum levels and disease activity, concerning either clinical, laboratory or instrumental findings. Our data show a significant deficit of klotho in SSc patients although any significant association was detected between klotho serum concentration and the clinical, laboratory or instrumental features of the disease. However, due to the limits of the study, further investigations are required.

Aseptic HLA B27-positive spondylodiscitis: decreased 18F-FDG uptake after etanercept treatment.

We observed a 69-year old man suffering from HLA B27 ankylosing spondylitis with persistent night back pain. 18F-FDG-PET/CT showed an increased metabolism at the level of the spinal space of L2-L3, L3-L4 with increased uptake compatible with spondylodiscitis. He started therapy with etanercept 50 mg/week. After six months of treatment repeated testing showed no uptake of the discs and vertebral bodies.

Pain in systemic sclerosis.

Chronic pain is a healthcare problem that significantly affects the mental health, and the professional and private life of patients. It can complicate many disorders and represents a common symptom of rheumatologic diseases, but the data on its prevalence is still limited. Pain is a ubiquitous problem in systemic sclerosis (SSc). SSc-related pain has been studied on the basis of biomedical models and is considered a symptom caused by the disease activity or previous tissue damage. Effective pain management is a primary goal of the treatment strategy, although this symptom in SSc has not yet been investigated in detail. However, these patients do not all respond adequately to pharmacological pain therapies, therefore in these cases a multimodal approach needs to be adopted. This paper must be considered as retracted due to a plagiarism misconduct. See the Retraction note at: https://doi.org/10.4081/reumatismo.2018.1171

Highlights on novel technologies for the detection of antibodies to Ro60, Ro52, and SS-B.

OBJECTIVE: We aimed to compare a chemiluminescent immunoassay (CIA, QUANTA Flash) on BIO-FLASH with a multiplex flow immunoassay (MFI) on BioPlex 2200 for the detection of antibodies to Ro60, Ro52, and SS-B. METHODS: The study included 241 samples, from patients suffering from systemic autoimmune diseases (n = 108) as well as disease controls (n = 133). All samples were tested for anti-Ro52, anti-Ro60, and anti-SS-B (La) antibodies on QUANTA Flash (INOVA Diagnostics, San Diego, USA) and BioPlex 2200 (Bio-Rad Laboratories Inc., Hercules, USA). Discrepant samples were tested by two independent methods: BlueDot/ANA and QUANTRIX Microarray (both D-tek, Belgium). RESULTS: The overall qualitative agreements were 95.4% (95% confidence interval, CI 92.0-97.7%) for anti-Ro52, 98.8% (95% CI 96.4-99.7%) for anti-Ro60, and 91.7% (95% CI 87.5-94.9%) for anti-SS-B antibodies. There were 34 discrepant samples among all assays (20 anti-SS-B, 11 anti-Ro52, 3 anti-Ro60). 30/33 of retested samples (by D-tek dot blot) agreed with the QUANTA Flash results. Similar findings were obtained with QUANTRIX Microarray kit. CONCLUSION: QUANTA Flash and BioPlex 2200 show good qualitative agreement. The clinical performances were similar for anti-Ro52 and anti-Ro60 autoantibodies while differences were observed for anti-SS-B (La) antibodies.

Granulomatosis polyangiitis associated with meningeal involvement: response to rituximab therapy after failure of cyclophosphamide.

Wegener's granulomatosis or granulomatosis polyangiitis associated (GPA) is a granulomatous inflammation of the upper and lower respiratory tracts associated with necrotising vasculitis of small and medium-sized blood vessels and, frequently, necrotising glomerulonephritis. We describe the case of a 37 year old female patient presenting with upper respiratory tract involvement, chronic rhinosinusitis with green secretions, and bilateral hypoacusia. Ten months later, she suffered occipital headache and two episodes of lipothymia associated with nausea, photophobia, faintness with visual blurring. Magnetic resonance imaging (MRI) revealed aseptic meningitis. The patient was treated with steroids and cyclophosphamide without any effect on the neurological symptoms which, however, greatly improved after subsequent treatment with rituximab as confirmed by means of cerebral MRI. Rituximab is an optimal means of treating cyclophosphamide-resistant patients with GPA associated with meningeal involvement.

Fibromyalgia and arthritides.

Fibromyalgia (FM) is a chronic pain syndrome that affects at least 2% of the adult population. It is characterised by widespread pain, fatigue, sleep alterations and distress, and emerging evidence suggests a central nervous system (CNS) malfunction that increases pain transmission and perception. FM is often associated with other diseases that act as confounding and aggravating factors, such as rheumatoid arthritis (RA), spondyloarthritides (SpA), osteoarthritis (OA) and thyroid disease. Mechanism-based FM management should consider both peripheral and central pain, including effects due to cerebral input and that come from the descending inhibitory pathways. Rheumatologists should be able to distinguish primary and secondary FM, and need new guidelines and instruments to avoid making mistakes, bearing in mind that the diffuse pain of arthritides compromises the patients' quality of life.

Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis factor-alpha blocking agents in rheumatoid arthritis.

Several smaller retrospective case series have concluded that leflunomide (LEF) in combination with anti-TNF-alpha blocking agents appears to be effective and safe. Prospective case series and cohort studies have generally confirmed the efficacy of this combination. Overall, there is currently no evidence from controlled trials that an anti-TNF-alpha combination with LEF is as effective as an anti-TNF-alpha combination with methotrexate (MTX). We compared the effectiveness and safety of a therapeutic regimen associating subcutaneous anti-TNF-alpha agents, etanercept (ETN) and adalimumab (ADA), with leflunomide (LEF) or methotrexate (MTX), in a two year open-label study performed in clinical practice. We evaluated 96 patients with active rheumatoid arthritis undergoing therapy with ADA at the dose of 40 mg every other week, or with ETN at the dose of 50 mg/week for two years added to prednisolone (PDN) at the mean dose of 5.2±2.6 mg/day. Fifty-four of these patients were also undergoing therapy with MTX at the mean dose of 11.7±2.6 mg/week, while 42 patients were undergoing therapy with LEF at the daily dose of 20 mg. At 12 months, the analysis of variance showed an improvement of DAS28 in both groups (p<0.001), with a reduction in 33.3% of the patients in treatment with LEF and in 51.8% of the patients in treatment with MTX (p = 0.20). At 18 months, improvement was present in 33.3% of the patients in the LEF group and in 81.5% of the patients in the MTX group (p=0.001). This improvement seems to be independent of the anti-TNF-alpha agent, even if MTX produces the highest DAS28 reduction when used in association with ETN (p<0.078). We found no difference in drug discontinuation rates or in effectiveness measures between anti-TNFalpha+MTX and anti-TNFalpha+LEF. Our data showed a greater reduction of DAS28 in the MTX group and, in combination with ETN, better results after two years of therapy.

Validation of a diagnostic score for the diagnosis of autoinflammatory diseases in adults.

Most autoinflammatory disorders typically come out in the pediatric population, although a limited number of patients may experience disease onset during adulthood. To date, a late disease onset has been described only in familial Mediterranean fever, caused by mutations in the MEFV gene, and in tumor necrosis factor receptor-associated periodic syndrome, caused by mutations in the TNFRSF1A gene. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that mutations will be found in an even smaller percentage of cases. With the aim of improving the genetic diagnosis in adults with suspected autoinflammatory disorders, we recently identified a set of variables related to the probability of detecting gene mutations in MEFV and TNFRSF1A and, in addition, we have also proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. In the present study we evaluated the preliminary score sensitivity and specificity on a wider number of patients in order to validate the goodness of fit of the model. Two hundred and nineteen consecutive patients with a clinical history of periodic fever attacks were screened for mutations in MEFV and TNFRSF1A genes; detailed information about family/personal history and clinical manifestations were also collected. For the validation of the score we considered data both from the 110 patients used to build the preliminary diagnostic score and from the additional 219 patients enrolled in the present study, for a total number of 329 patients. Early age at disease onset, positive family history for recurrent fever episodes, thoracic pain, abdominal pain and skin rash, which are the variables that had previously been shown to be significantly associated with a positive genetic test result (12), were used for validation. On univariate analysis the associations with a positive genetic test were: age at onset (odds ratio [OR] 0.43, p=0.003), positive family history for recurrent fever episodes (OR 5.81, p<0.001), thoracic pain (OR 3.17, p<0.001), abdominal pain (OR 3.80, p<0.001) and skin rash (OR 1.58, p=0.103). The diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic multivariate model (cut-off equals to 0.24) revealing good sensitivity (0.778) and good specificity (0.718). In conclusion, our score may serve in the diagnostic evaluation of adult patients presenting with recurrent fever episodes suspected of having an autoinflammatory disorder, helping identify the few subjects among them who may be carriers of mutations in MEFV and TNFRSF1A genes.

Rituximab in the treatment of rheumatoid arthritis patients in Italy: a budget impact analysis.

OBJECTIVES: The objective of this Budget Impact Analysis is to evaluate the financial implications of a rituximab-based sequencing strategy in the treatment of rheumatoid arthritis in the perspective of the Italian National Health Service. METHODS: Yearly patients who were eligible for a second-line biological DMARD in Italy were entered into a 5-year model. A Markov chain reproduced the course of this cohort under a number of alternative strategies, including anti-TNF-α cycling and rituximab or abatacept as second and third line agents. The dynamic of the simulation was given by first biological drug failure data, mortality rates, and survival-on-treatment data from published literature. Drug acquisition, administration and monitoring costs were assessed. RESULTS: Italian patients refractory to a first anti-TNF-α therapy resulted to be about 650 per year, giving a cumulative number of treated patients in five years of 3,240. The anti-TNF-α cycling had a total direct cost which rose from €8.2 million in the first year to €33.8 million in the fifth. The cost per patient of rituximab was lower than the average cost of the anti-TNF-α therapies; the annual difference was around € 4,300. The savings gained from lower individual costs with rituximab were partially offset by the increasing number of patients receiving active medication, resulting in a substantial cost equivalence between third line rituximab and anti-TNF-α cycling scenarios; rituximab, as a second line therapy, produced a savings in total costs of -31.8%. Strategies including abatacept shared the same dynamics, but with higher costs. CONCLUSIONS: The introduction of rituximab in clinical practice could allow an increase in the number of patients receiving an active rheumatoid arthritis treatment without inflating therapy costs.

Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature.

Tumor necrosis factor-alpha receptor (TNFR1)-associated periodic syndrome (TRAPS) is the most common autosomal-dominant autoinflammatory condition and is caused by mutations in the TNFRSF1A gene. TRAPS is characterized by recurrent attacks of fever typically lasting from 1 to 3 weeks; in addition to fever, common clinical features include mainly periorbital oedema, conjunctivitis, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthritis or arthralgia; serosal membrane inflammation is also possible. The identification of TNFRSF1A mutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent the primary therapeutic goal in TRAPS, thus disclosing new treatment choices for this complex disease. In the past few years, isolated reports and case-series have been published suggesting that inhibition of TNF-alpha might represent a promising therapeutic approach in TRAPS. We present here our experience with etanercept in the treatment of patients affected with TRAPS, and we also add a review of the literature.

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.

QuantiFERON-TB Gold and the TST are both useful for latent tuberculosis infection screening in autoimmune diseases.

Screening for active tuberculosis (TB) and latent TB infection (LTBI) is mandatory prior to the initiation of tumour necrosis factor-alpha inhibitor therapy. However, no agreement exists on the best strategy for detecting LTBI in this population. The aim of the present study was to analyse the performance of the tuberculin skin test (TST) and QuantiFERON-TB Gold in-tube (QFT-GIT) on LTBI detection in subjects with immunomediated inflammatory diseases (IMID). The TST and QFT-GIT were prospectively performed in 398 consecutive IMID subjects, 310 (78%) on immunosuppressive therapy and only 16 (4%) had been bacillus Calmette-Guérin (BCG) vaccinated. Indeterminate results to QFT-GIT were found in five (1.2%) subjects. Overall, 74 (19%) out of 393 subjects were TST-positive and 52 (13%) were QFT-GIT-positive. Concordance between TST and QFT-GIT results was good (87.7%): 13 were QFT-GIT-positive/TST-negative and 35 QFT-GIT-negative/TST-positive. By multivariate analysis both tests were significantly associated with older age. Only the TST was associated with BCG vaccination and radiological lesions of past TB. Use of immunosuppressive drugs differently modulated QFT-GIT or TST scoring. Use of the QuantiFERON-TB Gold in-tube, as a screening tool for latent tuberculosis among immunomediated inflammatory disease subjects, is feasible. Until further data will elucidate discordant tuberculin skin test/QuantiFERON-TB Gold in-tube results, a strategy of simultaneous tuberculin skin and QuantiFERON-TB Gold in-tube testing in a low prevalence bacillus Calmette-Guérin vaccinated population, should maximise potentials of latent tuberculosis diagnosis.

Correlation between atopy and hypersensitivity reactions during therapy with three different TNF-alpha blocking agents in rheumatoid arthritis.

OBJECTIVE: The use of TNF-alpha antagon-ists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety have been raised. Both acute and delayed reactions have been described. METHODS: The aim of our work was to detect if there is a different incidence of hypersensitivity reactions - infusion reactions to infliximab or injection site reactions with etanercept or adalimumab - in atopic patients versus non- atopic patients. In 90 patients (82 females, 8 males) with rheumatoid arthritis we evaluated, during the first year of therapy with three different TNF-alpha blocking agents, total serum IgE (normal value <100 KU/L) (method ImmunoCAP PHADIA) and serum specific IgE performing a qualitative multi-allergen test for inhal-ant allergens (PHADIATOP, method ImmunoCAP PHADIA). In all patients we evaluated injection site reactions (ISR) to etanercept and adalimumab - erythema, edema and itching at the site of subcutaneous administration - and infusion reactions to infliximab - hypotension/hypertension, chest pain, dyspnea, laryngospasm, fever, urticaria angioedema. RESULTS: We obtained the following results: patients with high value of tot-al IgE were 15/90 (16.6 %), patients with total IgE in normal range were 75/90 (83.4.%), reactions in patients with high total IgE were 6.7% and in patients with normal total IgE were 18.7% (p=0.255 ns). As regards serum specific IgE, patients with specific IgE were 17/90 (18.8%) patients without specific IgE were 73/90 (81.2%), reactions in patients with specific IgE were 11.8% and in patients without specific IgE were 17.8% (p=0.547 ns). Also, when the data were divided for the three groups, the differences were not statistically significant. CONCLUSION: Adverse reactions to biological agents have been categorized into five types. In hypersensitivity reactions - the Beta type reactions - an immune mechanism is suspected. Our data showed that there was no correlation between the atopic status and the incidence of hypersensitivity reactions during the first year of therapy with three different TNF-alpha blocking agents.

Effects of monthly intramuscular neridronate in rheumatic patients in chronic treatment with low-dose glucocorticoids.

OBJECTIVES: To assess the effects of intramuscular (im) neridronate (NE) on lumbar and femoral neck BMD and on markers of bone turnover in rheumatic patients under chronic low-dose glucocorticoids (GC) therapy. METHODS: Sixty-nine osteopoenic and osteoporotic patients, affected by rheumatic diseases and gastric or esophageal conditions which contraindicated treatment with oral bisphosphonates (BPs), were randomly assigned to: Group A (23 patients) administered with daily calcium 1 g and vitamin D 800 UI; Group B (46 patients) receiving daily calcium 1 g, vitamin D 800 UI and im NE 25 mg monthly. RESULTS: After 12 months of therapy (M12) lumbar BMD was reduced of 2.97% in Group A, and improved of 3.34% (p=0.001) in Group B; at M12, femoral neck BMD was reduced of 2.40% in Group A and improved of 1.78% in Group B (p=0.010). After 6 (M6) and 12 months of therapy, the bone resorption markers were significantly reduced in Group B: OHPr-41.64% at M6 (p<0.001) and -37.91% at M12 (p<0.001); DPD-33.4% at M6 (p<0.001) and -33.18% (p<0.001) at M12: NTX -57.08% (p<0.001) at M6 and -55.95% (p<0.001) at M12; OC-11.62% (p=0.05) at M6 and -12.62% at M12 (p=0.06); B-ALP -13.95 % at M6 (p=0.04) and -0.85% at M12 (NS). CONCLUSION: A twelve-month intramuscular NE treatment in rheumatic patients under GCs therapy improves lumbar and femoral BMD and mainly reduces the markers of bone resorption.

The economic burden of biological therapy in rheumatoid arthritis in clinical practice: cost-effectiveness analysis of sub-cutaneous anti-TNFalpha treatment in Italian patients.

Rheumatoid arthritis (RA), with a prevalence of 0.46%, is found in about 272,004 patients in Italy. The socioeconomic cost of rheumatoid arthritis in Italy in 2002 has been estimated at Euro 1,600 million. Cost-effectiveness evaluations have been based on the concept that, with treatment, patients will not progress to the next level(s) of disease severity or will take a longer time to progress, thus avoiding or delaying the high costs and low utility associated with more severe disease. Many cost-effective studies have been based on the variation of Health Assessment Questionnaire (HAQ) in clinical trials. The objective of this study is to perform a cost-effective analysis of 86 patients with rheumatoid arthritis in therapy with adalimumab 40 mg every other week and etanercept 50 mg/week for two years in a population of patients observed in clinical practice. The group of patients in therapy with adalimumab had also taken methotrexate, mean dose 12.4+/-2.5 mg/week (22 patients) or leflunomide 20 mg/day (16 patients). The group of patients in therapy with etanercept had also taken methotrexate, mean dose 11.7+/-2.6 mg/week (24 patients) or leflunomide 20 mg/day (24 patients). Incremental costs and QALYs (quality adjusted life years) gains are calculated compared with baseline, assuming that without biologic treatment patients would remain at the baseline level through the year. Conversion HAQ scores to utility were based on the Bansback algorithm. The results after two years showed: in the group methotrexate+adalimumab the QALY gained was 0.62+/-0.15 with a treatment cost of Euro 26,517.62 and a QALY/cost of Euro 42,521.13. In the group methotrexate + etanercept the QALY gained was 0.64+/-0.26 with a treatment cost of Euro 25,020.96 and a QALY/cost of Euro 39,171.76. The result of using etanercept in association with methotrexate is cost-effectiveness with a QALY gained under the acceptable threshold of Euro 50,000. These are important data for discussion from an economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice.