Marta Favero

Novel aspects of Sjögren’s syndrome in 2012

Sjögren’s syndrome (SS) is a systemic progressive autoimmune disease characterized by a complex pathogenesis requiring a predisposing genetic background and involving immune cell activation and autoantibody production. The immune response is directed to the exocrine glands, causing the typical ‘sicca syndrome’, but major organ involvement is also often seen. The etiology of the disease is unknown. Infections could play a pivotal role: compared to normal subjects, patients with SS displayed higher titers of anti-Epstein-Barr virus (EBV) early antigens, but lower titers of other infectious agent antibodies such as rubella and cytomegalovirus (CMV) suggest that some infections may have a protective role against the development of autoimmune disease. Recent findings seem to show that low vitamin D levels in patients with SS could be associated with severe complications such as lymphoma and peripheral neuropathy. This could open new insights into the disease etiology. The current treatments for SS range from symptomatic therapies to systemic immunosuppressive drugs, especially B cell-targeted drugs in cases of organ involvement. Vitamin D supplementation may be an additional tool for optimization of SS treatment.

Rheumatoid arthritis is the major risk factor for septic arthritis in rheumatological settings.

Septic arthritis (SA) is a clinical emergency with considerable morbidity and mortality that can lead to rapid joint destruction and irreversible functional loss. The reported incidence varies from 2-5 cases/100,000 person-years in the general population to 70 cases/100,000 person-years among patients with rheumatoid arthritis. In fact, individuals with rheumatoid arthritis are at particular risk for developing SA. This may be due to several reasons: joint disease predisposes to bacterial joint colonization and RA itself and its treatment with corticosteroids, disease-modifying antirheumatic drugs (DMARDs) and biological therapies may decrease the immune function required for protection from pathogens. Steroids and DMARDs seem to affect the leukocyte synovial count; indeed, RA patients with SA have a leukocyte count in synovial fluid (SF) lower than patients with SA without underlying rheumatic diseases. The diagnosis of SA in RA patients can be difficult because the development of a hot painful joint is often confused with a relapse of the underlying joint disease leading to delay in diagnosis. For this reason the microscopic analysis and culture of synovial fluid are crucial to exclude septic arthritis.

A hyaluronic acid-salmon calcitonin conjugate for the local treatment of osteoarthritis: chondro-protective effect in a rabbit model of early OA.

Osteoarthritis (OA) is characterized by chronic degeneration of joints, involving mainly the articular cartilage and the underlying bone, and severely impairing the quality of life of the patient. Although with limited efficacy, currently available pharmacological treatments for OA aim to control pain and to retard disease progression. Salmon calcitonin (sCT) is a drug which has been shown to have therapeutic effects in experimental arthritis by inhibiting both bone turnover and cartilage degradation and reducing the activities of matrix metalloproteinases (MMP). High molecular weight hyaluronic acid (HA) is used as a lubricant in OA therapy, and, interestingly, HA polymers may normalize the levels of MMP-1, -3 and -13. We demonstrated that sCT rapidly clears from the knee joint of rat animal model, after intra-articular (i.a.) administration, and it induces systemic effects. Here, sCT was conjugated to HA (200kDa) with the aim of prolonging the residence time of the polypeptide in the joint space by reducing its clearance. An aldehyde derivative of HA was used for N-terminal site-selective coupling of sCT. The activity of sCT was preserved, both in vitro and in vivo, after its conjugation and the i.a. injection of HA-sCT did not trigger any systemic effects in rats. The efficacy of HA-sCT treatment was tested in a rabbit OA model and clear chondro-protective effect was proven by macro- and microscopic assessments and histological findings. Our results indicate that HAylation of sCT increases the size of the polypeptide in a stable covalent manner and delays its passage into the blood stream. We conclude that HA conjugation prolongs the anti-catabolic effects of sCT in joint tissues, including the synovial membrane and cartilage.

Early knee osteoarthritis

Concepts regarding osteoarthritis, the most common joint disease, have dramatically changed in the past decade thanks to the development of new imaging techniques and the widespread use of arthroscopy that permits direct visualisation of intra-articular tissues and structure. MRI and ultrasound allow the early detection of pre-radiographic structural changes not only in the peri-articular bone but also in the cartilage, menisci, synovial membrane, ligaments and fat pad. The significance of MRI findings such as cartilage defects, bone marrow lesions, synovial inflammation/effusions and meniscal tears in patients without radiographic signs of osteoarthritis is not fully understood. Nevertheless, early joint tissue changes are associated with symptoms and, in some cases, with progression of disease. In this short review, we discuss the emerging concept of early osteoarthritis localised to the knee based on recently updated knowledge. We highlight the need for a new definition of early osteoarthritis that will permit the identification of patients at high risk of osteoarthritis progression and to initiate early treatment interventions.

Human chondrocyte cultures as models of cartilage-specific gene regulation.

The human adult articular chondrocyte is a unique cell type that has reached a fully differentiated state as an end point of development. Within the cartilage matrix, chondrocytes are normally quiescent and maintain the matrix constituents in a low-turnover state of equilibrium. Isolated chondrocytes in culture have provided useful models to study cellular responses to alterations in the environment such as those occurring in different forms of arthritis. However, expansion of primary chondrocytes in monolayer culture results in the loss of phenotype, particularly if high cell density is not maintained. This chapter describes strategies for maintaining or restoring differentiated phenotype by culture in suspension, gels, or scaffolds. Techniques for assessing phenotype involving primarily the analysis of synthesis of cartilage-specific matrix proteins as well as the corresponding mRNAs are also described. Approaches for studying gene regulation, including transfection of promoter-driven reporter genes with expression vectors for transcriptional and signaling regulators, chromatin immunoprecipitation, and DNA methylation are also described.

Italian Society of Rheumatology recommendations for the management of gout

OBJECTIVE Gout is the most common arthritis in adults. Despite the availability of valid therapeutic options, the management of patients with gout is still suboptimal. The Italian Society of Rheumatology (SIR) aimed to update, adapt to national contest and disseminate the 2006 EULAR recommendations for the management of gout. METHODS The multidisciplinary group of experts included rheumatologists, general practitioners, internists, geriatricians, nephrologists, cardiologists and evidence-based medicine experts. To maintain consistency with EULAR recommendations, a similar methodology was utilized by the Italian group. The original propositions were translated in Italian and priority research queries were identified through a Delphi consensus approach. A systematic search was conducted for selected queries. Efficacy and safety data on drugs reported in RCTs were combined in a meta-analysis where feasible. The strength of recommendation was measured by utilising the EULAR ordinal and visual analogue scales. RESULTS The original 12 propositions were translated and adapted to Italian context. Further evidences were collected about the role of diet in the non-pharmacological treatment of gout and the efficacy of oral corticosteroids and low-dose colchicine in the management of acute attacks. Statements concerning uricosuric treatments were withdrawn and replaced with a proposition focused on a new urate lowering agent, febuxostat. A research agenda was developed to identify topics still not adequately investigated concerning the management of gout. CONCLUSIONS The SIR has developed updated recommendations for the management of gout adapted to the Italian healthcare system. Their implementation in clinical practice is expected to improve the management of patients with gout.

Septic Arthritis Caused by Rothia dentocariosa in a Patient with Rheumatoid Arthritis Receiving Etanercept Therapy

To the Editor: Rothia dentocariosa is a pleomorphic gram-positive rod normally found in the human mouth that has been associated with dental cavities, periodontal disease1, and, rarely, as a cause of systemic infection2,3. We describe a case of septic arthritis due to R. dentocariosa in a 46-year-old woman admitted to our Rheumatology Unit in December 2008. She had been diagnosed with polyarticular rheumatoid arthritis (RA) 10 years before, and for 2 years arthritis was treated with etanercept (25 mg twice weekly) and oxaprozin. She underwent a meniscectomy and synovectomy of the right knee in March 2008. Tumor necrosis factor (TNF) inhibitor was stopped 2 weeks before and started again 2 weeks after surgery. Levofloxacin was administered for 2 weeks after surgery. Three months later the knee suddenly became swollen and painful. The patient had no fever; laboratory investigation showed only a mild increase of erythrocyte sedimentation rate (ESR; 57 mm/h). Arthritis was diagnosed as a rheumatoid flare and treated with corticosteroid infiltrations, unsuccessfully, with no other therapeutic change. On admission, … Address correspondence to Prof. Schiavon; E-mail: f.schiavon{at}unipd.it

Bartter’s and Gitelman’s diseases

Bartters and Gitelmans syndromes are two different genetic renal diseases, but are both characterised by hypokalaemia and metabolic alkalosis. Bartters syndrome is characterised by multiple gene mutations (Na-K-2Cl cotransporter; K(+) channels renal outer medullary potassium channel (ROMK); Cl channels, chloride channel Kb (ClCNKb); regulatory protein Barttin; and Ca(2+) -sensing receptor, CaSR) at the thick ascending limb of Henles loop, while Gitelmans syndrome is caused by a mutation in the gene encoding the renal thiazide sensitive Na(+)-Cl(-) cotransporter, located in the apical membrane of the distal convoluted tubule. The co-existence of hypokalaemia with hypomagnesaemia and hypocalciuria represents the biochemical hallmark of Gitelmans syndrome that distinguishes it from Bartters syndrome. Calcium pyrophosphate deposition (CPPD) including chondrocalcinosis has been frequently reported in association with Bartters syndrome. Some authors postulate that these cases were probably due to Gitelmans syndrome and not due to Bartters syndrome as all patients had hypomagnesaemia. This electrolyte disorder seems to induce CCP crystal deposition. To date, no cases of CPPD have been reported in patients who had Bartters syndrome without hypomagnesaemia. CPPD may be found in other conditions associated with hypomagnesaemia, such as short bowel syndrome or tacrolimus therapy in liver transplantation patients. As acute CPP crystal arthropathy or pseudogout can be the onset presentation of Gitelmans syndrome, CPPD should be considered a major feature of this disease. Rheumatologists should be aware of the association between Gitelmans syndrome and CPPD, and should consider this metabolic disorder when CPPD occurs in younger patients.

Systemic and Local Adipose Tissue in Knee Osteoarthritis: OBESITY AND FAT PAD IN KNEE OSTEOARTHRITIS

Osteoarthritis is a common chronic joint disorder affecting older people. The knee is the major joint affected. The symptoms of osteoarthritis include limited range of motion, joint swelling, and pain causing disability. There are no disease modifying drugs available, and treatments are mainly focused on pain management. Total knee replacement performed at the end stage of the disease is considered the only cure available. It has been found that obese people have an increased risk to develop not only knee but also hand osteoarthritis. This supports the concept that adipose tissue might be related to osteoarthritis not only through overloading. As matter of fact, obesity induces a low grade systemic inflammatory state characterized by the production and secretion of several adipocytokines that may have a role in osteoarthritis development. Furthermore, hypertension, impaired glucose, and lipid metabolism, which are comorbidities associated with obesity, have been shown to alter the joint tissue homeostasis. Moreover, infrapatellar fat pad in the knee has been demonstrated to be a local source of adipocytokines and potentially contribute to osteoarthritis pathogenesis. Here, we discuss the role of systemic and local adipose tissue in knee osteoarthritis. J. Cell. Physiol. 232: 1971–1978, 2017.

Peptide Receptor Radionuclide Therapy in a Case of Multiple Spinal Canal and Cranial Paragangliomas

Case Report In 2000, a 32-year-old man was admitted to the hospital with lower back pain. Gadolinium-enhanced lumbar (L1-S1) magnetic resonance imaging (MRI) revealed a clearly delimited, ovoid, expansive, intradural mass with a strong contrast enhancement behind the L4 vertebral body, occupying the vertebral foramina, mildly scalloping the vertebral body. MRI findings were interpreted as caudal ependymoma. After radical surgery, the symptoms vanished. The tumor mass measured 3 2.5 2 cm and had a yellowish brown cut surface with hemorrhagic and cystic foci. The specimens were fixed in 10% buffered formalin and embedded in paraffin. Sections (3 m thick) were stainedwithhematoxylinandeosin(Fig1A; 10),Grimelius Masson trichrome (Bio-Optica, Milano, Italy), and periodic acid-Schiff (PAS; Merck, Darmstadt, Germany). Immunohistochemical analyses were carried out by using synaptophysin (Fig 1B; 10; positive stain), CD56 (Fig 1C; 20; positive stain), avidin-biotin complex method for low-molecular-weight cytokeratin (Fig 1D; 10; punctiform expression of anticytokeratin marker [CAM 5.2]), somatostatin, serotonin, neuronspecific enolase, Leu-7, inhibin, and S-100 protein. A positive SDHB immunohistochemistry (Fig 1E; 10) was also reported. At light microscopy, the tumors presented as solid proliferation of round cells with eosinophilic cytoplasm and regular, monomorphic, oval central nuclei in an alveolar arrangement (Zellballen pattern) surrounded by thin capillaries and a flattened layer of sustentacular cells. Pleomorphism, mitotic figures, and bizarre nuclear forms were occasionally seen. Positive expression of chromogranin A and synaptophysin and the presence of chief (type 1) cells were consistent with the neuroendocrine nature of the tumor. Few sustentacular cells were positive for S-100 protein, and immunoreactivity for glial