Can adipokines serum levels be used as biomarkers of hand osteoarthritis?

PURPOSE: To evaluate serum levels of visfatin, resistin and adiponectin in patients with erosive (E) and non-erosive (NE) osteoarthritis (OA) of the hand (HOA) compared to normal controls (NC). METHODS: 94 outpatients with E HOA and NE HOA and 21 NC were enrolled. The radiological assessment of both hands was performed according to the Kellgren-Lawrence and Kallman score. Patients were divided into two subsets (lone HOA or generalized OA) based on clinically OA involvement of knee and hip. Serum visfatin, resistin and adiponectin levels were determined by ELISA assay. RESULTS: Visfatin was significantly higher in E HOA patients in comparison to NC and NE HOA group. Resistin showed a significant increase in both E HOA and NE HOA groups versus NC, in particular in generalized OA. No significant differences among groups were found in adiponectin. The Kallman score was more severe in the two subsets of E HOA patients compared to NE HOA. CONCLUSIONS: This study showed increased levels of resistin in erosive and non-erosive HOA, and higher visfatin levels in E HOA in comparison to NE HOA. These data suggest the adipokines possible role in the pathogenesis of HOA and their potential usefulness as biomarkers of the disease.

Real-world experience of tocilizumab in rheumatoid arthritis: sub-analysis of data from the Italian biologics' register GISEA.

To assess the long-term effectiveness and safety of tocilizumab, abatacept, and tumor necrosis factor-α inhibitors (TNFi), in the Italian real-world setting of rheumatoid arthritis (RA). The records of adult RA patients from the Italian biologics' registry Gruppo Italiano Studio Early Arthritis (GISEA) were analyzed. Demographic and clinical data were obtained at entry. The disease remission rate (28-joint disease activity score calculated using the erythrocyte sedimentation rate [DAS28-ESR] ≤ 2.6) and frequency of adverse events (AEs) were evaluated at 2 years. From 1999 to 2014, 7539 patients were treated with biologics (61.3% in first- and 22.6% in second-line), 68% of cases received TNFi, 9.1% tocilizumab, and 8.6% abatacept. Treatment groups showed a similar DAS28 at entry. As first-line, tocilizumab induced a significantly higher remission rate than abatacept or TNFi at 6 (51 vs 23.3 and 26.2%, respectively; p < 0.0001) and 24 months (52.3 vs 33.3 and 34.4%, respectively; p < 0.01). A similar pattern was observed in later lines. The most common AEs reported were infections, reactions to biologics (more frequent among TNFi-treated patients), increased transaminase (more frequent among TCZ-treated patients), and cardiovascular events. In clinical practice, TCZ induced a rapid and long-lasting remission and in a higher percentage of patients compared to abatacept and TNFi, with a good safety profile.

Immunometabolic biomarkers of inflammation in Behçet's disease: relationship with epidemiological profile, disease activity and therapeutic regimens.

Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied, current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR), interleukin (IL)-6 and serum amyloid A (SAA) serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimens. Serum concentrations of sTNFR (P = 0·008), leptin (P = 0·0011), sCD40L (P < 0·0001) and IL-6 (P = 0·0154) were significantly higher in BD patients than in HC, while no difference was found in MCP-1, MPO and resistin serum levels. Moreover, we observed significantly higher sTNFR serum concentrations in BD patients presenting inactive disease than HC (P = 0·0108). A correlation between sTNFR and age was also found, with higher levels in patients over 40 years than HC (P = 0·0329). Although further research is warranted to elucidate the role of circulating biomarkers, some of that may contribute to the understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach.

Chronic pelvic pain: comorbidity between chronic musculoskeletal pain and vulvodynia.

Chronic pelvic pain (CPP) is a common condition that has a major impact on the quality of life of both men and women. Male CPP is usually attributable to well-defined urogenital conditions (most frequently infectious/non infectious prostatic diseases) or musculoskeletal or bowel diseases, whereas the features of female CPP are much more complex and are of particular clinical and epidemiological importance. It is a multifactorial syndrome that can be due to diseases of the urogenital, gastrointestinal, or musculoskeletal systems, or to neurological or neuropsychiatric disorders. It is not always easy to identify its predominant pathogenesis, although it often occurs as a central sensitization syndrome triggered by an initial stimulus which is no longer detectable and only manifests itself clinically through pain. In this respect, there are some very interesting relationships between vulvodynia and fibromyalgic syndrome, as identified in a preliminary study of women with chronic musculoskeletal pain in which it was demonstrated that vulvar pain plays an important role, although it is often overlooked and undiagnosed.

Prevalence of Baker's cyst in patients with knee pain: an ultrasonographic study.

The objectives of this study are to investigate the prevalence of Baker's cyst (BC) in patients with knee pain, and to assess the correlation between BC and severity of osteophytes and joint effusion. A retrospective study was conducted on a group of patients with knee pain referred to our outpatient clinic for ultrasonography of the knee between January 2010 and February 2011. Patients underwent an ultrasonographic exam of the knees to assess the presence of marginal femorotibial osteophytosis, joint effusion and BC. A dichotomous score was assigned to each item (1 present, 0 absent) and severity of US signs of osteoarthritis and joint effusion were also graded semiquantitatively. Collected data were processed using logistic regression analysis to evaluate the correlation between degree of osteophytosis and joint effusion and BC. Patients affected by inflammatory joint conditions or with history of joint surgery or recent trauma were excluded. A total of 399 patients with knee pain were studied (299 women), in the age range 18-89 years (mean 56.2, SD 16.3 years). 293 patients (73.4%) showed sonographic features of osteoarthritis and 251 (62.9%) joint effusion. BC was found in 102 patients (25.8%) together with a positive association with sonographic features of osteoarthritis and joint effusion. Our data show a prevalence of BC of 25.8% in a population of patients with knee pain, and suggest that BC is positively related to osteoarthritis and joint effusion. Ultrasonographic examination of knee is worthwhile in patients with painful osteoarthritis or evidence of effusion.

Expanding spectrum of TNFRSF1A gene mutations among patients with idiopathic recurrent acute pericarditis.

Although idiopathic recurrent acute pericarditis (IRAP) is generally presumed to derive from an autoimmune process, increasing interest is currently being devoted to autoinflammatory diseases, a group of disorders of the innate immune system caused by mutations of genes involved in the regulation or activation of the inflammatory response, without any apparent involvement of autoimmunity. The tumour necrosis factor receptor-1-associated periodic syndrome is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding the 55-kD receptor for tumour necrosis factor-α. IRAP patients carrying TNFRSF1A gene mutations have been recently described. We report herein the first IRAP patients carrying the rare R104Q and D12E TNFRSF1A gene mutations, thus expanding the spectrum of tumour necrosis factor receptor-1-associated periodic syndrome mutations in IRAP patients.

Serum leptin, resistin, visfatin and adiponectin levels in tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

OBJECTIVES: The aims of our study were to evaluate serum leptin, resistin, visfatin and adiponectin levels in patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS), in comparison to healthy controls, and to correlate their levels to parameters of disease activity and/or severity. METHODS: Serum leptin, resistin, visfatin and adiponectin levels were obtained from 14 TRAPS patients carrying mutations involving cysteine residues, from 16 TRAPS patients carrying other mutations, and from 16 healthy controls. Demographic, clinical and laboratory parameters, including amyloidosis were entered for each patient. Comparisons between groups as well as reciprocal comparisons have been evaluated. RESULTS: Serum leptin, resistin, visfatin and adiponectin did not significantly differ among the 3 groups. Patients carrying cysteine residues mutations showed lower visfatin serum levels than patients carrying other mutations (p<0.02). Serum leptin significantly correlated with the number of attacks/year (multiple R=0.32, multiple adjusted R2= 0.19, p <0.03). Serum adiponectin levels significantly correlated with the presence of amyloidosis (multiple R=0.79, multiple adjusted R2=0.57, p<0.03). Adiponectin values were a significant predictor for amyloidosis (AUC 0.75, 95 CI: 0.56-0.94, p<0.03), with a predicting cut-off value set at 23.16 pg/ml, the predictive positive value was 53.8%. Visfatin serum levels resulted respectively related to leptin (rs=0.42, r2=0.18, p<0.02) and to resistin (rs=0.57, r2=0.32, p<0.01) serum levels; whilst leptin and resistin serum levels did not reciprocally correlate. CONCLUSIONS: Although a prospective design study and larger cohort are mandatory, adipokines serum levels and their correlations with parameters of disease activity and/or severity seem to show a baseline pattern in TRAPS patients.

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.

A novel ex vivo organotypic culture model of alkaptonuria-ochronosis.

OBJECTIVES: Alkaptonuria (AKU) is an orphan disease that has an estimated prevalence of 0.3/100,000. The disease is caused by the lack of activity of homogentisic acid oxidase (HGO), an enzyme involved in tyrosine and phenylalanine metabolism. To date, there is only one drug, the nitisinone, with orphan designation authorised by both Food and Drug Administration (FDA) and European Medical Agency (EMA) for AKU. A clinical trial on AKU patients using nitisinone has recently been completed but it needs further investigation for long-term therapy. In recent years our group has developed a series of AKU in vitro models using cell lines, primary chondrocytes and human plasma in order to test the efficacy of new substances, mainly antioxidant compounds, for AKU therapy. Herein, we report the optimisation of an ex vivo reproducible culture method exploiting cartilage slices in order to investigate the deposition of ochronotic pigment in this kind of connective tissue. METHODS: Human normal cartilage slices, obtained after surgery for prosthesis replacement, were cultured for several days in the presence of a sublethal concentration of homogentisic acid (HGA). RESULTS: After two months of incubation with HGA, the peculiar melanin-like ochronotic pigmentation can be observed into the cartilage tissue. CONCLUSIONS: This novel organo-typic ex vivo model could be extremely useful to investigate the efficacy of substances able to ameliorate the conditions of AKU patients. Moreover, it could be used for genetic and proteomic investigations to better define AKU pathophysiology.

[The laboratory approach in the diagnosis of systemic autoinflammatory diseases]. / L'approccio laboratoristico nella diagnostica delle malattie autoinfiammatorie sistemiche.

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immunity characterized by the recurrence of febrile attacks lasting from few hours to few weeks and multi-district inflammation of different severity involving skin, serosal membranes, joints, gastrointestinal tube and central nervous system. The vast majority of these conditions is caused by mutations in genes involved in the control of inflammation and apoptosis mechanisms. The group includes familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, hereditary pyogenic and granulomatous disorders. Their diagnostic identification derives from the combination of clinical and biohumoral data, though can be sometimes confirmed by genotype analysis.

Evaluation of the effect of Bosentan treatment on proinflammatory cytokine serum levels in patients affected by Systemic Sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular and fibrotic changes in the skin and in internal organs. Endothelin-1 (ET-1) is a peptide that has a role in promoting both vascular injury and the fibrotic process in SSc; indeed, patients with systemic sclerosis have higher levels of ET-1 compared with healthy subjects. Moreover, ET-1 enhances expression of pro-inflammatory cytokines in animal model. Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension and digital ulcers in scleroderma patients. In animal models and in vitro models, after treatment with Bosentan, a significant reduction of cytokine (TNF α, IFN γ,IL-8, IL-4) levels was observed. The aim of the study is to verify whether Bosentan treatment in SSc patients can reduce circulating cytokines levels. We enrolled 10 patients affected by SSc with digital ulcers and/or pulmonary hypertension, treated with Bosentan 125 mg twice daily. Patients were tested for cytokines and ET-1 level before treatment and after 12 months. The cytokines tested were IL-10, IL-2, IL-4, IL-5, IL-6, IL-8, GM-CSF, IFN-γ and TNF. Levels of ET-1, IL-10, IL-4, IL-5, GM-CSF and TNFalpha did not show consistent modification during treatment with Bosentan in respect to baseline, while IL-2, IL-6, IL-8 and IFN-γ were significantly decreased. Bosentan significantly reduced IL-2, IL-6, IL-8 and IFN- γ levels in SSc patients, probably slowing progression to fibrosis and vascular damage. This is the first report showing a decrease of profibrotic and proinflammatory cytokines levels in humans during treatment with Bosentan.

Ultrasonography vs. clinical examination in children with suspected arthritis. Does it make sense to use poliarticular ultrasonographic screening?

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a term that encompasses all forms of arthritis that begin before the age of 16 years old, persist for more than 6 weeks and are of unknown cause. The ILAR criteria for JIA classification are based on the number of joints involved. The aim of our study was to compare clinical evaluation and ultrasonography (US) in the assessment of joint synovitis in children with suspected JIA. METHODS: We enrolled in our study all children who presented at our outpatient clinic of Paediatric Rheumatology with suspected JIA. All the children underwent a clinical examination for joint swelling (40 joints), a tender joint count (42 joints) and US examination (42 joints) on the same day. They all returned to the clinic after approximately 2 weeks with the results of the tests prescribed at the first visit and a diagnosis was formulated. RESULTS: Thirty-one children were enrolled. More synovitis was identified by US than by than clinical examination (42 joints vs. 27). Clinical examination classified as swollen 13 joints that did not result affected at US. Of the 94 painful joints, 24 were affected by synovitis at US. The final diagnoses were: 9 children with JIA (any form), 9 were classified as healthy and 13 with other diseases. One child was reclassified and 2 were diagnosed with JIA thanks to US. CONCLUSIONS: US detected more synovitis than clinical examination in children with suspected JIA, therefore, US should be included in the screening procedure of children with suspected JIA.

Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes.

Cryopyrin-associated periodic syndromes are categorized as a spectrum of three autoinflammatory diseases, namely familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous articular syndrome. All are caused by mutations in the NLRP3 gene coding for cryopyrin and result in active interleukin-1 release: their rarity and shared clinical indicators involving skin, joints, central nervous system and eyes often mean that correct diagnosis is delayed. Onset occurs early in childhood, and life-long therapy with interleukin-1 blocking agents usually leads to tangible clinical remission and inflammatory marker normalization in a large number of patients, justifying the need to facilitate early diagnosis and thus avoid irreversible negative consequences for tissues and organs.

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.

Ultrasonographic and functional changes of the ulnar nerve at Guyon's canal after carpal tunnel release.

OBJECTIVE: To describe morphologic and functional modifications of the ulnar nerve at the wrist in carpal tunnel syndrome (CTS) after carpal tunnel release (CTR). METHODS: Ultrasonography was used to study the cross sectional area (CSA) of the ulnar nerve at Guyon's canal, before and 1 and 6 months after CTR, in 18 CTS patients. A parallel electrophysiological and clinical analysis was also conducted. RESULTS: CSA of the ulnar nerve significantly increased 6 months after CTR. Ten (55%) cases showed abnormal CSA values compared to a control group before surgery and five (28%) at 6 month follow-up. In addition, there were improvements in the motor and sensory ulnar axon recruitment properties and the conduction values in sensory ulnar fibres. Patients with extra-median distribution of paresthesia (4 subjects) were free from symptoms. CONCLUSIONS: CTR has a significant effect not only on the anatomical geometry of Guyon's canal, but also on the morphology and function of the ulnar nerve. SIGNIFICANCE: In CTS, high pressure in the carpal tunnel may result in anatomical changes of ulnar nerve, thus causing functional impairment to the ulnar fibres. CTR appears to reverse some of this damage.

Development and preliminary validation of a diagnostic score for identifying patients affected with adult-onset autoinflammatory disorders.

To date, the rate of detection of autoinflammatory gene mutations in patients suspected of having an autoinflammatory disorder is very low. However, most of these data refer to pediatric populations. 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. Our aim was to develop and validate a set of variables for predicting the risk that a given adult patient presenting with recurrent fever episodes carries mutations in the MEFV or TNFRSF1A genes, in order to increase the probability of obtaining positive results on genetic testing. One hundred and ten consecutive patients with a clinical history of periodic fever attacks were screened for mutations in the TNFRSF1A and the MEFV genes. The mean age at disease onset was 27.85 years. Detailed information about each patient?s family history, personal history, and clinical manifestations were retrospectively collected. A diagnostic score was constructed based on univariate and multivariate analysis in a randomly-selected dataset (training set; n=40). The score was validated on an independent set of the remaining patients (validation set; n=70). Age at onset (odds ratio 0.958, P =0.050), positive family history of recurrent fever episodes (OR 5.738, P = 0.006 ), thoracic pain (OR 7.390, P = 0.002), abdominal pain (OR 2.853, P = 0.038) and skin involvement (OR 8.241, P = 0.003) were independently correlated with a positive genetic test result. A diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic model (cut off equal to 0.24) revealing high sensitivity (0.94), high specificity (0.94) and high accuracy (0.94). We have identified variables that appear to be strongly related to the probability of detecting gene mutations in MEF and TNFRSF1A in adults, thus improving the evaluation of patients with suspected autoinflammatory disorders.

[Copernican revolution in the therapy of rheumatoid arthritis: the contribution of anti-TNFalpha drugs]. / La rivoluzione copernicana nella terapia dell'artrite reumatoide: il contributo degli anti-TNFalpha.

TNFalpha has a key role in cell recruitment, proliferation and death, expression of adhesion molecules and immune responses. In RA, TNFalpha is involved in matrix degradation and osteoclastogenesis. TNFalpha inhibitors are either soluble receptors (etanercept) or monoclonal antibodies (infliximab and adalimumab; golimumab and certolizumab are in development). TNFalpha antagonists, alone or in combination with methotrexate, reduce bone erosions and thinning of cartilage, but they differ as regards ligand binding, pharmacokinetics, pharmacodynamics, and clinical indications. Etanercept is the only TNFalpha antagonist that also neutralises LFT-alpha. Infliximab and adalimumab are more immunogenic. Cytotoxicity and cellular lysis are also higher with infliximab and adalimumab. Etanercept slows progression of joint damage in recently diagnosed RA when given alone, but much more when given with methotrexate; anti-TNF monoclonal antibodies also were shown to slow progression alone and in combination with methotrexate. Patients with early and long-standing RA treated with etanercept have now shown improvement in ACR scores, inflammation and disability for up to 9 years. Outcomes with infliximab and adalimumab are similar to those with etanercept, but only in combination with methotrexate. As a result of neutralizing antibodies, increasing doses of anti-TNFalpha antibodies may be required to maintain clinical response. As regards side effects, opportunistic infections seem more frequent with monoclonal antibodies. TNFalpha antagonists produce more QALYs than traditional DMARDs, counteracting higher costs. The efficacy, safety, and quality of life benefits of TNFalpha antagonists suggest using them possibly earlier than today, even in clinically moderate RA. Thanks to its overall profile, etanercept might be considered as one of the first-choices in TNFalpha antagonism in RA management.