Distinct tribological endotypes of pathological human synovial fluid reveal characteristic biomarkers and variation in efficacy of viscosupplementation at reducing local strains in articular cartilage.

OBJECTIVE: Viscosupplementation has been used for decades to treat mild to moderate osteoarthritis, yet it is unknown if the lubricating function of different pathological synovial fluids (SF) vary, or if they respond differentially to viscosupplementation. The objectives of this study were to (i) evaluate the friction coefficients and induced shear strains in articular cartilage when lubricated with pathological SF, (ii) identify the effect of hyaluronic acid (HA) supplementation on friction coefficients and shear strains, and (iii) identify SF biomarkers that correlate with lubricating function. METHOD: Human pathological SF was grouped by white blood cell count (inflammatory: >2000 cells/mm3, n = 6; non-inflammatory: <2000 cells/mm3, n = 6). Compositional analyses for lubricin and cytokines were performed. Friction coefficients and local tissue shear strain measurements were coupled using new, microscale rheological analyses by lubricating neonatal bovine cartilage explants with SF alone and in a 1:1 ratio with HA (Hymovis®). RESULTS: Friction coefficients were not significantly different between the inflammatory and non-inflammatory pathologies (p = 0.09), and were poorly correlated with peak tissue strains at the cartilage articular surface (R2 = 0.34). A subset of inflammatory SF samples induced higher tissue strains, and HA supplementation was most effective at lowering friction and tissue strains in this inflammatory subset. Across all pathologies there were clear relationships between polymorphonuclear neutrophil (PMN), IL-8, and lubricin concentrations with cartilage tissue strains. CONCLUSION: These results suggest that pathological SF is characterized by distinct tribological endotypes where SF lubricating behaviors are differentially modified by viscosupplementation and are identifiable by biomarkers.

Effect of an oral preparation containing hyaluronic acid, chondroitin sulfate, hydrolyzed collagen type II and hydrolyzed keratin on synovial fluid features and clinical indices in knee osteoarthritis. A pilot study.

The aim of this study was to evaluate the effect of an oral preparation containing a naturally occurring matrix of hydrolyzed collagen type II, chondroitin sulfate (CS), and hyaluronic acid (HA), and bioactive oligopeptides of natural hydrolyzed keratin (K) in patients affected by knee OA through the evaluation of synovial fluid (SF) and clinical changes before and after treatment. Thirty patients with knee OA and swollen joint were included in the study and submitted to arthrocentesis. Patients were randomized in two groups: 1) the treatment group (N.15) took a dietary supplement containing 120 mg HA, 240 mg CS and 300 mg K once a day for 4 weeks; 2) the control group (N.15) was only submitted to arthrocentesis. Patient symptoms were evaluated at the beginning and at the end of the study by the WOMAC self-assessment questionnaire, the Lequesne algofunctional index, and the VAS forms. SF changes were evaluated by measuring local inflammatory indices, cytokines IL-1ß, IL-8, IL-6, IL-10 and GM-CSF. The group of patients treated with the oral supplement showed an improvement in the clinical indices WOMAC (p<0.01), Lequesne (p=0.014) and VAS pain (p<0.01). On the contrary, no significant changes were found in the control group. The SF collected from the treated group showed a reduction of IL-8 (p=0.015), IL-6 and IL-10 levels, while no changes in cytokines were observed in the control group. This pilot study suggests that an oral administration of a preparation containing a combination of HA, CS and K can improve some clinical parameters and affect cytokine concentrations in SF in patients with knee OA.

Biomarkers, imaging and disease activity indices in patients with early axial spondyloarthritis: the Italian arm of the SpondyloArthritis-Caught-Early (SPACE) Study.

The study aimed to evaluate biomarkers facilitating early diagnosis of axial spondyloarthritis (axSpA) and correlations between them and disease activity parameters and imaging indexes. Patients with low back pain (LBP) (≥3 months, ≤2 years, onset ≤45 years) participating in the Italian arm of the SpondyloArthritis-Caught-Early SPACE study underwent a physical examination, questionnaires, laboratory tests, X-rays and MRI of the spine and sacroiliac joints (SIJ). An expert rheumatologist formulated axSpA diagnosis in accordance with Assessment of SpondyloArthritis International Society (ASAS) criteria. Disease activity and physical functioning were assessed using imaging, clinical and serological indices. Spine and SIJ MRI and X-rays were scored independently by 2 readers using the SPARCC, mSASSS and NY-criteria. Patients were classified as: subjects with signs of radiographic sacroiliitis (r-axSpA), subjects with signs of sacroiliitis on SIJ-MRI but not on X-rays (nr-axSpA MRI SIJ+) or subjects with no signs of sacroiliitis on MRI/X-rays but with >2 SpA features and signs of bone oedema on MRI spine (nr-axSpA MRI SIJ-/undifferentiated SpA). Significant differences were found in the prevalence of radiographic sacroiliitis, active sacroiliitis on MRI and SPARCC SIJ scores. Biomarker levels were not significantly increased in any of the patient groups. The correlations between IL-17 and IL-23 and other indices were not significant; correlations were found between IL-22 and BASFI, BASG1, HAQ, VAS pain, between mSASSS and MMP3, and between the latter and hsCRP. Although not significantly higher in any of the three groups, IL-22, MMP3 and hsCRP values were correlated with some disease activity indexes and with mSASSS. Large observational studies are required to confirm these preliminary findings.

Synovial fluid proteins are required for the induction of interleukin-1ß production by monosodium urate crystals.

OBJECTIVES: Monosodium urate (MSU) crystal deposition in gouty joints promotes the release of inflammatory mediators, in particular interleukin (IL)-1ß. The induction of IL-1ß production by MSU crystals requires a co-stimulus. The objective of this study was to determine which part of the synovial fluid (SF) provides co-stimulation to MSU crystals to induce IL-1ß in macrophages. METHOD: The lipidic fraction (LF) and the protein fraction (PF) were isolated from the SF of patients with arthropathies. The PF was subfractionated according to different molecular weight (MW) ranges. THP-1 cells or human primary monocytes were stimulated with MSU crystals in the presence or absence of SF or SF fractions. IL-1ß and IL-8 production and IL-1ß mRNA expression were assessed by an enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR). RESULTS: Exposure of monocytes/macrophages to MSU crystals alone induced the moderate release of IL-8 but not of IL-1ß. The production of IL-1ß required the presence of both SF from patients with inflammatory arthritis (SFi) and MSU crystals. SF from patients with non-inflammatory arthritis, that is patients with osteoarthritis (OA), did not affect the IL-1ß production but slightly enhanced the secretion of IL-8. Both MSU crystals and SFi were required for the induction of the IL-1ß transcript, which was not expressed in the presence of either stimulus alone. SFi fractionation demonstrated that the MSU crystal co-stimulus was contained in the PF of SFi with MW > 50 kDa but not in the LF. CONCLUSIONS: This study shows that the SF of inflammatory arthritis patients, including gout patients, contains proteins required for the induction of IL-1ß by MSU crystals in macrophages whereas lipids are not involved.

Spine and sacroiliac joints on magnetic resonance imaging in patients with early axial spondyloarthritis: prevalence of lesions and association with clinical and disease activity indices from the Italian group of the SPACE study.

Our aim was to determine the prevalence of spine and sacroiliac joint (SIJ) lesions on magnetic resonance imaging (MRI) in patients with early axial spondyloarthritis (axSpA) and their correlation with disease activity indices. Sixty patients with low back pain (LBP) (≥3 months, ≤2 years, onset ≤45 years), attending the SpA-clinic of the Unità Operativa Complessa Reumatologia of Padova [SpondyloArthritis-Caught-Early (SPACE) study], were studied following a protocol including physical examination, questionnaires, laboratory tests, X-rays and spine and SIJ MRI. Positive spine and SIJ MRI and X-rays images were scored independently by 2 readers using the SPARCC method, modified Stoke ankylosing spondylitis spine score and New York criteria. The axial pain and localization of MRI-lesions were referred to 4 sites: cervical/thoracic/lumbar spine and SIJ. All patients were classified into three groups: patients with signs of radiographic sacroiliitis (r-axSpA), patients without signs of r-axSpA but with signs of sacroiliitis on MRI (nr-axSpA MRI SIJ+), patients without signs of sacroiliitis on MRI and X-rays (nr-axSpA MRI SIJ-). The median age at LBP onset was 29.05±8.38 years; 51.6% of patients showed bone marrow edema (BME) in spine-MRI and 56.7% of patients in SIJ-MRI. Signs of enthesitis were found in 55% of patients in the thoracic district. Of the 55% of patients with BME on spine-MRI, 15% presented presented a negative SIJMRI. There was a significant difference between these cohorts with regard to the prevalence of radiographic sacroiliitis, active sacroiliitis on MRI and SPARCC SIJ score. The site of pain correlated statistically with BME lesions in thoracic and buttock districts. Since positive spine-MRI images were observed in absence of sacroiliitis, we can hypothesize that this finding could have a diagnostic significance in axSpA suspected axSpA.

Pain and microcrystalline arthritis.

Microcrystals are responsible for some of the most common and complex arthropathies which are often accompanied by intense, severe pain and inflammatory reactions. The main pathogens are crystals of monosodium urate (MSU), responsible for the gout, calcium pyrophosphate (CPP), which deposits also in various clinical forms of arthopathies, and basic calcium phosphate associated with osteoarthritis. In this context, the microcrystal arthritis is characterized by multiple, acute attacks followed by chronic pain, disability, impaired quality of life, and increased mortality. Given their chronic nature, they represent an ever more urgent public health problem. MSU and CPP crystals are also able to activate nociceptors. The pain in mycrocrystalline arthritis (MCA) is an expression of the inflammatory process. In the course of these diseases there is an abundant release of inflammatory molecules, including prostaglandins 2 and kinins. Interleukin-1 represents the most important cytokine released during the crystal-induced inflammatory process. Therefore, clinically, pain is the most important component of MCA, which lead to functional impairment and disability in a large proportion of the population. It is fundamental to diagnose these diseases as early as possible, and to this aim, to identify appropriate and specific targets for a timely therapeutic intervention.

Metabolism of crystals within the joint.

Monosodium urate (MSU), calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals deposit in joints and surrounding tissues causing acute inflammation and chronic cartilage damage. A number of endogenous substances and physicochemical conditions affect their precipitation, growth and even dissolution, regulating their metabolism and inflammatory activity. We review how MSU and calcium crystals form within the joints and the various factor which regulate their formation.

Synovial colony-stimulating factor-1 mRNA expression in diffuse pigmented villonodular synovitis.

OBJECTIVES: To delineate the molecular mechanisms underlying the process of the diffuse-type giant cell tumours, also called pigmented villonodular synovitis, a rare, aggressive condition of the synovium, the knee synovial tissue expression of colony-stimulating factor-1 gene, as detected by real-time polymerase chain reaction, was compared between patients affected with pigmented villonodular knee synovitis and knee meniscal tears, or persistent gonoarthitis. METHODS: Multiple synovial biopsies of the knee were performed by arthroscopy in five consecutive patients affected by diffuse pigmented villonodular knee synovitis and in 12 patients affected by knee meniscal tears (n. 6) or persistent active gonarthritis (n. 6), recruited from the patients attending the Rheumatology Day Surgery Outpatient Clinic of the University of Padova Hospital. The ethics committee approved the study protocol and the participants signed consent statements after being informed about the content of the study. The diagnosis was made on the basis of a histological examination. The colony-stimulating factor-1 gene expression was assessed by reverse transcription followed by real-time polymerase chain reaction. RESULTS: The detection by RT-PCR of synovial colony-stimulating factor-1 mRNA showed a wide spectrum of expression in the three groups of distinct knee joint disease affected patients, with significantly higher level of colony-stimulating factor-1 mRNA expression in synovial tissue of pigmented villonodular synovitis, in comparison to that of knee meniscal injuries and persistent gonoarthritis patients. CONCLUSIONS: Our findings point out to an important role of colony-stimulating factor-1 in pigmented villonodular knee synovitis disease process and support the idea that colony-stimulating factor-1/colony-stimulating factor-1 receptor interaction may represent a potential therapeutic target of this disease.

[HDL inhibit cytokine production in a mouse model of urate crystal-induced inflammation]. / Le HDL inibiscono la produzione di citochine nel modello murino di infiammazione da microcristalli di urato monosodico.

OBJECTIVES: To evaluate whether high density lipoproteins (HDL) affect monosodium urate (MSU) crystal-induced inflammation in the murine air pouch model. METHODS: MSU crystals were prepared by Denko's method and sterilized by heating at 180°C for 2 h before each experiment. Human HDL were isolated from peripheral blood of healthy volunteers. MSU crystals (2 mg in 1 ml of PBS) were injected into subcutaneous air pouches in mice in the presence or absence of HDL (0.1 mg). Negative control pouches received 1 ml of PBS. To recover pouch fluid, the pouches were washed with 2 ml of PBS after the animals were sacrificed. The leukocyte count in the lavage fluids was obtained using a hemocytometer and differential leukocyte count was determined by May-Grunwald-Giemsa staining. IL-6, KC, CCL2 and TNF-α levels were measured in exudates by ELISA. RESULTS: MSU crystals increased the number of leukocytes and the neutrophil migration, as well as the concentrations of IL-6, KC and CCL2 in pouch fluids, while the TNF-α levels were not detectable. The treatment with HDL led to a reduction in all inflammatory parameters: the leukocyte count decreased by 73%; the neutrophil density decreased by 35%; the IL-6, KC and CCL2 concentration decreased by 4-, 6- and 5-fold respectively. CONCLUSIONS: This study shows that HDL may limit the inflammatory process by inhibiting leukocyte recruitment and cytokine release. HDL are likely to represent a mechanism of control of crystal-induced inflammation.

Apolipoprotein A-I and cholesterol in synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis.

OBJECTIVE: To investigate lipid and apolipoprotein (Apo) levels in synovial fluid (SF) and serum of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and osteoarthritis (OA). METHODS: SF of 44 patients (14 RA, 14 PsA, 16 OA) was tested for Apo A-I, HDL-C, total cholesterol (TC), IL-1Beta, TNF-alpha, white blood cell count (WBC) and polymorphonucleate (PMN) percentage. Blood samples, collected simultaneously to the SF, were examined for Apo A-I, HDL-C, TC, TNF-alpha, serum amyloid A (SAA) and C-reactive protein (CRP). Thirty-three healthy donors served as a control group. RESULTS: Serum levels of Apo A-I, HDL-C and TC were higher in OA as compared with RA, PsA and the control group. The patients with inflammatory arthritis had lower serum levels of Apo A-I and HDL-C than did the controls. Apo A-I concentrations were higher in SF of RA patients, while PsA showed the highest concentration of TC, though not reaching statistical significance. A negative correlation was found between serum Apo A-I and synovial WBC (r=-0.48 p=0.002) and IL-1Beta (r=-0.42 p=0.016). There was a strong positive correlation between the Apo A-I SF/serum ratio and synovial WBC (r=0.73 p<0.001), IL-1Beta (r=0.68 p<0.001) and a weak, yet significant, correlation with serum CRP (r=0.49 p=0.002) and SAA (r=0.41 p=0.008). CONCLUSION: Our study confirms that in RA Apo A-I and TC levels are decreased in plasma and increased in SF, thus suggesting infiltration of HDL particles in the inflamed joint with inhibition of the local production of proinflammatory cytokines. On the other hand, it can be hypothesized that the sequestration of Apo A-I in the inflamed tissue may, in part, account for the reduction of circulating HDL and the excess cardiovascular risk in RA and PsA patients.

[The mediterranean diet model in inflammatory rheumatic diseases]. / Il modello nutrizionale mediterraneo nelle malattie reumatiche infiammatorie.

The Mediterranean diet is based on a pattern of eating closely tied to the Mediterranean region, which includes Greece and southern Italy. Essentially, the traditional diet emphasizes foods from plant sources, limited meat consumption, small amounts of wine and olive oil as the main fat source. The beneficial effects of the Mediterranean diet has been proven not only to cardiovascular diseases but also for diabetes, obesity, arthritis and cancer. Its anti-inflammatory and protective properties are linked to the large presence of omega-3 polyunsaturated fatty acids, vitamins, but especially to the constituents of extra virgin olive oil: oleic acid, phenolic compounds olecanthal, a new recently discovered molecule, with natural anti-inflammatory properties. It has been shown that the Mediterranean diet can reduce disease activity, pain and stiffness in patients with inflammatory arthritis and may thus constitute a valuable support for patients suffering from these diseases.

[Fish oil supplementation in rheumatoid arthritis]. / La supplementazione dietetica con olio di pesce nell'artrite reumatoide.

The beneficial properties of fish oil are well known and are related to its fatty acid composition rich in omega-3 polyunsaturated fatty acids. In the last years a variety of epidemiological and clinical studies have demonstrated the efficacy of fish oil supplementation in the rheumatic diseases, in particular in rheumatoid arthritis. The anti-inflammatory effects of fish oil are linked to the production of alternative eicosanoids, to the reduction of proinflammatory cytokines, to the inhibition of the activation of T lymphocytes and of catabolic enzymes. Fish oil supplementation could represent a valuable support to the traditional pharmacological treatment of rheumatoid arthritis.

[Role of omega-3 polyunsaturated fatty acids in diet of patients with rheumatic diseases]. / Ruolo degli acidi grassi omega-3 nella dieta dei pazienti affetti da patologie reumatiche infiammatorie.

The beneficial effects of omega-3 polyunsaturated fatty acids have been widely described in the literature in particular those on cardiovascular system. In the last decade there has been an increased interest in the role of these nutrients in the reduction of articular inflammation as well as in the improvement of clinical symptoms in subjects affected by rheumatic diseases, in particular rheumatoid arthritis (RA). Nutritional supplementation with omega-3 may represent an additional therapy to the traditional pharmacological treatment due to the anti-inflammatory properties which characterize this class of lipids: production of alternative eicosanoids, reduction of inflammatory cytokines, reduction of T-lymphocytes activation, reduction of catabolic enzymes activity. The encouraging results of dietetic therapy based on omega-3 in RA are leading researchers to test their effectiveness on patients with other rheumatic conditions such as systemic lupus erythematosus and ankylosing spondylitis. Nutritional therapy based on food rich in omega-3 or on supplementation with fish oil capsules, proved to be a valid support to he treatment of chronic inflammatory rheumatic diseases.

[Synoviocyte cultures from synovial fluid]. / Realizzazione di colture di sinoviociti da liquido sinoviale.

UNLABELLED: The study of the pathogenetic mechanisms of rheumatic diseases is in general carried out through "in vitro" systems based on cellular cultures models. The difficulties to achieve fresh human tissue prompted us to develop a simpler method to obtain fibroblast-like synovial cells from synovial fluid (SF). METHODS: SF was collected from the knees of 5 patients with rheumatoid arthritis (RA), 4 with osteoarthritis (OA) and 5 with psoriatic arthritis (PsA). The pellet obtained after centrifugation was resuspended in DMEM/HamF12 containing 10% foetal calf serum, 1% peni-streptomycin, 4 ng/ml of fibroblast grow factor and incubated at 37 degrees C in T25 culture flasks. Synoviocytes were also obtained from fresh synovial membranes (SM) by explants technique. Both types of cells were characterized by immunocytochemistry and their inflammatory response to synthetic monosodium urate crystals was studied through the measurement of nitric oxide (NO). RESULTS: Adherent synoviocytes were obtained from the culture of 2/5 SF from RA, 4/4 SF from OA and 5/5 SF from PsA. Synoviocytes isolated from both SF and SM expressed surface antigens CD90, CD55, and the intracellular prolyl-4-hydroxylase. Morphologically, the cells showed the typical spindle-shape fibroblast-like appearance. NO levels induced by UMS crystals in SF synoviocytes were similar to those obtained in SM synoviocytes. CONCLUSION: Adherent cells obtained from SF showed the phenotype and the reactivity of tissue synoviocytes. Due to the easy accessibility of SF, this method may represents an useful alternative when synovial tissues is not promptly available.

Laboratory findings in psoriatic arthritis.

Psoriatic arthritis (PsA) has been classically defined as an inflammatory arthritis associated with psoriasis. However, in comparison with other relevant inflammatory arthropathies, in which a definite diagnosis is frequently possible only by means of laboratory investigations, in PsA true laboratory diagnostic markers are lacking. Some markers are utilised more to differentiate other diseases than to characterise PsA. For example in polyarticular PsA, which may be in some cases indistinguishable from RA, the rheumatoid factor (RF) or the more specific and recently introduced antibodies to cyclic citrullinated peptides (anti-CCP), may be useful to better identify RA. However, RF was found in 5% to 13% of patients with PsA, and anti-CCP may be observed in almost similar percentage. The determination of ESR and/or CRP is frequently disappointing in PsA, since they are both elevated in only half of the patients with PsA. However, ESR and/or CRP are included in the most utilised response criteria for RA, such as ACR and DAS, and, in addition are also considered reliable in the assessment of PsA. Furthermore, elevated levels of ESR have been proposed as one of the best predictors of damage progression and, in addition, a low ESR seems protective, while an ESR >15 mm/h is one of the factors associated with an increased mortality in PsA. The synovial fluid (SF) effusion is much higher in PsA, in comparison with other arthropathies. When available, SF analysis may offer additive information useful for the diagnosis, such as the increased number of leukocytes, which underlines the inflammatory nature of the effusion even in a patient with normal serum levels of acute phase response. We found that elevated IL-1 levels in SF of patients with early disease (<6 months), may be predictive of an evolution in polyarticular form at follow-up. This observation is in keeping with the crucial role that inflammatory cytokines play in PsA, probably related to a genetic predisposition. The recent introduction in PsA of anti-TNF-alpha agents and the demonstration of their efficacy in the management of many clinical disease expressions including peripheral arthropathy, axial involvement, enthesopathy and skin manifestations, have stimulated the research also in the field of the possible laboratory markers.

[Intra-articular treatment with the TNF-alpha antagonist, etanercept, in severe diffuse pigmented villonodular synovitis of the knee]. / Trattamento intra-articolare con l'antagonista del TNFalpha etanercept nella sinovite villo-nodulare pigmentosa diffusa del ginocchio.

Pigmented villonodular synovitis (PVNS) is a rare pre-malignant disease that require aggressive treatment as surgical synovectomy, eventually followed by radiosynovectomy. Nevertheless, the disease often reoccurs after these treatments. To determine the safety and efficacy of intra-articular (IA) TNFalpha blockade with etanercept (ETN), before extended arthroscopic synovectomy, in severe PVNS of the knee, two patients, (a 26-year-old man with B27+ undifferentiated spondylarthropathy and a 32-year-old femal with seronegative oligoarthritis), affected by diffuse knee PVNS (diagnosis made by histological examination), resistant to IA corticosteroid injections and to repeated arthroscopic synovectomy, were submitted, after protocol approval by human research committee and patient's written informed consent to intra-articular etanercept (IA-ETN) treatment with a different dosage schedule: 12.5 mg weekly IA-ETN injection for 4 weeks, followed by extended arthroscopic synovectomy and of 25 mg IA-ETN injection for 4 weeks, respectively. Previous DMARDs treatment was continued in stable appropriate doses. Any adverse events were recorded throughout the study. The following parameters were considered as clinical endpoints: 1) Knee Joint Index (KJI: range 0-14); 2) Thompson index (THI: range 0-9) At the study entry and at the end of follow-up, high frequency ultrasound grey scale synovial thickening (US-ST) was also assessed. No adverse events were observed due to IA-ETN and to arthroscopic synovectomy. Marked improvement of knee disease activity over time and sustained functional recover was obtained. US-ST evaluation before treatment initiation and at the end of follow-up confirmed the regression of knee joint synovial proliferation.

[Detection and identification of crystals in synovial fluid]. / La ricerca dei microcristalli nel liquido sinoviale.

Synovial fluid analysis for crystals represents one of the most important laboratory test for the evaluation of rheumatic diseases. The identification of monosodium urate and calcium pyrophosphate dihydrate crystals allows the prompt diagnosis of gout and pyrophosphate crystal-related arthropaties. Crystals are identified based on their shape and birefringence through a polarized light microscope equipped with a first order red compensator. Due to its simple execution and high diagnostic value, this examine should be always performed to complete synovial fluid analysis.

[The enthesopathy of vitamin D-resistant osteomalacia in adults]. / La polientesopatia dell'osteomalacia vitamina D resistente dell'adulto.

A case of an adult patient with vitamin D-resistant osteomalacia or X-linked hypophosphatemic osteomalacia (XLH) with diffuse calcification of entheses is reported. XLH is the most frequent cause of rickets in developed countries. It is characterized by an impaired renal transport of the phosphate and mutation of PFEX (phosphate regulating gene, with homologies to endopeptidase on the X-chromosome). In childhood, the classic clinical presentation includes short stature and bow leg. While at this age the main radiographic features are characterised by rickets, in adult life they are dominated by a generalised calcific enthesopathy. Concerning the pathogenesis of the enthesopathic lesions of XLH, no convincing hypothesis has yet been made. As in our patient, the extension and the severity of enthesopathy seems not related to the severity of the biochemical changes nor to the treatment with calcitriol. The calcified enthesopathy is an integral part of XLH and it is possible that it is found in adult because many years are necessary to produce it.

Molecular mechanisms of pain in crystal-induced arthritis.

Crystal-induced arthritis (CIA) is characterized by an intense inflammatory reaction triggered by the deposition of monosodium urate, calcium pyrophosphate, and basic calcium phosphate crystals in articular and periarticular tissues. Severe, acute pain constitutes the most important clinical symptom in patients affected by these diseases. Pain along with redness, warmness, swelling, and stiffness in the affected joint arises abruptly in gout and disappears when the acute phase of the attack resolves. While an acute joint attack caused by calcium pyrophosphate crystals can mimic a gout flare, basic calcium phosphate crystal arthritis gives rise to a series of clinical manifestations, the most severe of which are calcific periarthritis, mostly asymptomatic, and a highly destructive arthritis known as Milwaukee shoulder syndrome, which is characterized by painful articular attacks. Pain development in CIA is mediated by several inflammatory substances that are formed after cell injury by crystals. The most important of these molecules, which exert their effects through different receptor subtypes present in both peripheral sensory neurons and the spinal cord, are prostaglandins, bradykinin, cytokines (in particular, interleukin (IL)-1ß), and substance P. The pharmacological treatment of pain in CIA is strictly associated with the treatment of acute phases and flares of the disease, during which crystals trigger the inflammatory response. According to international guidelines, colchicines, nonsteroidal anti-inflammatory drugs, and/or corticosteroids are first-line agents for the systemic treatment of acute CIA, while biologics, namely anti-IL-1ß agents, should be used only in particularly refractory cases.