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Objective The aim of the study is to assess the performance of the DACTOS (DACtylitis glObal Sonographic) score in a PsA dactylitis clinical setting. In particular, we evaluated the ability of DACTOS to identify the affected fingers, its sensitivity to change after treatment, the correlations between DACTOS and clinical parameters, and the capacity of the score to identify the treatment responders. Methods Forty-six consecutive patients with symptomatic PsA hand dactylitis were enrolled. A total of seventy-three dactylitic digits were evaluated clinically and sonographically before and after treatment in this observational and prospective study. Clinical assessment included the Leeds Dactylitis Index-basic (LDI-b) score and visual analogue scales for pain (VAS-p) and functional impairment (VAS-FI). Sonographic lesions were investigated using high-frequency ultrasound with grey scale and power Doppler features according to the DACTOS score. Correlations between the DACTOS score and the clinical parameters were assessed at baseline, 1 month (T1) and 3 months (T3). Results We observed significant improvements in all of the assessed clinical parameters and the DACTOS scores after dactylitis treatment. There was a statistically significant correlation between the variation of all clinical parameters (VAS-p, VAS-FI and LDI-b) and the DACTOS score at T1 and T3 evaluations. We found statistically significant differences in the DACTOS score between clinical responder and non-responder groups (P Conclusion The DACTOS score performs well in real-life clinical settings in terms of sensitivity to change and correlations with clinical features in PsA dactylitis.

ObjectivesMast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). However, their contribution remains controversial. To establish their role in RA, we analysed their presence in the synovium of treatment-naïve patients with early RA and their association and functional relationship with histological features of synovitis.MethodsSynovial tissue was obtained by ultrasound-guided biopsy from treatment-naïve patients with early RA (n=99). Immune cells (CD3/CD20/CD138/CD68) and their relationship with CD117+MCs in synovial tissue were analysed by immunohistochemistry (IHC) and immunofluorescence (IF). The functional involvement of MCs in ectopic lymphoid structures (ELS) was investigated in vitro, by coculturing MCs with naïve B cells and anticitrullinated protein antibodies (ACPA)-producing B cell clones, and in vivo in interleukin-27 receptor alpha (IL27ra)-deficient and control mice during antigen-induced arthritis (AIA).ResultsHigh synovial MC counts are associated with local and systemic inflammation, autoantibody positivity and high disease activity. IHC/IF showed that MCs reside at the outer border of lymphoid aggregates. Furthermore, human MCs promote the activation and differentiation of naïve B cells and induce the production of ACPA, mainly via contact-dependent interactions. In AIA, synovial MC numbers increase in IL27ra deficient mice, in association with ELS and worse disease activity.ConclusionsSynovial MCs identify early RA patients with a severe clinical form of synovitis characterised by the presence of ELS.

Blau syndrome (BS) and early onset sarcoidosis (EOS) are, respectively, the familial and sporadic forms of the pediatric granulomatous autoinflammatory disease, which belong to the group of monogenic autoinflammatory syndromes. Both of these conditions are caused by mutations in the NOD2 gene, which encodes the cytosolic NOD2 protein, one of the pivotal molecules in the regulation of innate immunity, primarily expressed in the antigen-presenting cells. Clinical onset of BS and EOS is usually in the first years of life with noncaseating epithelioid granulomas mainly affecting joints, skin, and uveal tract, variably associated with heterogeneous systemic features. The dividing line between autoinflammatory and autoimmune mechanisms is probably not so clear-cut, and the relationship existing between BS or EOS and autoimmune phenomena remains unclear. There is no established therapy for the management of BS and EOS, and the main treatment aim is to prevent ocular manifestations entailing the risk of potential blindness and to avoid joint deformities. Nonsteroidal anti-inflammatory drugs, corticosteroids and immunosuppressive drugs, such as methotrexate or azathioprine, may be helpful; when patients are unresponsive to the combination of corticosteroids and immunosuppressant agents, the tumor necrosis factor-α inhibitor infliximab should be considered. Data on anti-interleukin-1 inhibition with anakinra and canakinumab is still limited and further corroboration is required. The aim of this paper is to describe BS and EOS, focusing on their genetic, clinical, and therapeutic issues, with the ultimate goal of increasing clinicians' awareness of both of these rare but serious disorders.

BACKGROUND: Nucleotide-binding oligomerization domain 2 (NOD2) is a key intracellular protein of the innate immune system. NOD2 variants are associated with inflammatory bowel disease (IBD) and other inflammatory phenotypes. We described the case of a baby with a very early-onset IBD who is characterized by a rare homozygous variant in NOD2, found through whole-exome sequencing, Its pathogenic effect was investigated through bioinformatics and functional studies. METHODS: The microbicide activity of the patient's phagocytes was analyzed using Escherichia coli. HEK293 and Caco2 cell lines were transfected with wild-type and mutated NOD2 cDNA to evaluate the NF-kB activity and the protein distribution. The functionality of the NOD2 pathway was assessed through analysis of the expression of tumor nectrosis factor alpha (TNFα) on monocytes. The levels of various cytokines were quantified in the patient plasma by a multiplex suspension array. RESULTS: A missense NOD2 mutation, c.G1277A; p.R426H in homozygosis, was found. The patient's microbicide activity was comparable to that observed in controls. HEK293 cells transfected with the mutated cDNA showed a 20-fold increase of NF-kB activation in basal condition. Moreover, Caco2 immunostaining revealed a different cytoplasmic distribution of the mutated protein compared with wild-type. A higher production of TNFα by monocytes and elevated levels of plasmatic cytokines and chemokines were evidenced in the patient. CONCLUSIONS: This homozygous mutation is functionally relevant and shows a different NOD2 involvement in the IBD phenotype. In our patient, this mutation caused a gain of function typical of the Blau syndrome phenotype, manifesting, however, an IBD-like phenotype.

Objective To systematically review the role of musculoskeletal US in patients suffering from PsA or psoriasis (Pso) in terms of prevalence, diagnosis, prognosis, monitoring and treatment. Methods A systematic literature review was conducted through medical databases (MEDLINE via PubMed, Embase) and the grey literature up to September 2015 to inform a new study of the Musculoskeletal Ultrasound Study Group of the Italian Society for Rheumatology. All articles reporting data on musculoskeletal US in PsA or Pso were included and extracted according to the underlying clinical question. Results A total of 86 publications were included. The prevalence of US abnormalities showed a wide range for each examined feature (e.g. 37-95% for entheses thickness of the lower limbs). The performance of US for diagnosis of disease or elementary lesions was variable across studies, but no study evaluated the overall performance of US in addition to clinical findings for diagnosing PsA. Considering US in defining PsA and Pso prognosis, several works focused on US of entheses of lower limbs in Pso, while for the monitoring of PsA activity five different scoring systems were identified. Last, the results of the role of US in guiding intra-articular interventions were controversial for the clinical outcomes, but in favour of US for accuracy. Conclusion despite the recognized importance of US in the management of PsA and Pso, this review clearly demonstrated the need of pivotal research in order to optimize the use of US in the diagnosis and monitoring of psoriatic disease.

Objectives: To test the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) and disease activity score in 44 and 28 joints (DAS, DAS28) definitions of remission in early rheumatoid arthritis (RA), against disability and ultrasound-detectable synovitis. Methods: In an observational study of early RA patients, remission rates were determined and compared in 166 patients. The remission definitions included the simplified disease activity index (SDAI≤3.3), ACR/EULAR (categorical), DAS28 (

We describe an immunocompetent 61-year-old woman who was negative for human immunodeficiency virus and who had recurrent human herpesvirus 8 (HHV-8) infection associated with a relapsing systemic inflammatory syndrome characterized by fever, lymphadenopathy, splenomegaly, edema, arthrosynovitis, and rash. Kaposi's sarcoma developed 10 months after the initial clinical presentation. A correlation was documented between the recurrent clinical manifestations and the HHV-8 load in plasma and peripheral-blood mononuclear cells. Histologic examination of an enlarged lymph node heavily infected with HHV-8 revealed an atypical lymphoproliferative disorder characterized by paracortical hyperplasia and collapsed primary and secondary follicles.

Treatment of monogenic autoinflammatory disorders, an expanding group of hereditary diseases characterized by apparently unprovoked recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells, has been revolutionized by the discovery that several of these conditions are caused by mutations in proteins involved in the mechanisms of innate immune response, including components of the inflammasome, cytokine receptors, receptor antagonists, and oversecretion of a network of proinflammatory molecules. Aim of this review is to synthesize the current experience and the most recent evidences about the therapeutic approach with biologic drugs in pediatric and adult patients with monogenic autoinflammatory disorders.

Objectives To investigate whether children with juvenile idiopathic arthritis (JIA) in clinical remission have subclinical synovial disease on ultrasound, and whether ultrasound abnormalities predict an early flare of synovitis. Methods Thirty-nine consecutive children who had clinically defined inactive disease (ID) for a minimum of 3 months underwent ultrasound assessment of 52 joints. All joints were scanned for synovial hyperplasia, joint effusion, power Doppler (PD) signal and tenosynovitis. Patients were then followed clinically for up to 2 years until a flare of synovitis occurred in one or more joints, or until the 2-year visit if the disease remained in clinical remission. Results Synovial hyperplasia, joint effusion, PD signal and tenosynovitis in at least one joint were detected in 76.9%, 66.7%, 33.3% and 15.4% of patients, respectively. During the 2-year follow-up, 24 patients (61.5%) experienced sustained ID, whereas 15 patients (38.5%) had a flare of synovitis in a total of 45 joints after a median of 10.6 months (range 6.3–13.7 months). At study entry, the rate of synovial hyperplasia, joint effusion and tenosynovitis was comparable between patients with persistent ID and patients with synovitis flare, whereas patients with persistent ID had a greater frequency of PD signal than patients with synovitis flare. Only 17 of the 45 flared joints had ultrasound abnormalities at study entry. Conclusion The authors found that ultrasound-detected synovial abnormalities are common in children with JIA in clinical remission. However, the presence of ultrasound pathology did not predict an early flare of synovitis in the affected joints.

Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous recurrent uveitis, dermatitis and symmetric arthritis. The gene responsible for BS has been identified in the caspase recruitment domain gene CARD15/NOD2. In the majority of patients, the disease is characterized by early onset, usually before 3-4years of age. The manifestations at disease onset are usually represented by articular and cutaneous involvement signs, generally followed later by ocular manifestations which are often the most relevant morbidity of BS. In some cases the presence of fever is also observed; atypical cases of BS have been reported with cardiovascular, neurological, renal, intestinal and other organ involvement. The rarity and the variations in the severity and evolution of its expressions do not permit sufficient data about optimal treatment for patients with BS. The first step of therapy is represented by the use of corticosteroids and successively, in case of unsatisfactory response, by additional treatment with immunosuppressive agents. The results with biologic anti-cytokine agents, such as anti-TNFα and anti-IL1β, are different, particularly with regard to ocular morbidity. Clinical and genetic aspects of the familial and the sporadic form of BS will be discussed and focused on. A description of a case study of an Italian family is also included.

Objective: The aims of our study were to investigate the prevalence of ultrasound (US) abnormalities in the foot of patients with rheumatoid arthritis (RA) and to compare them with the clinical findings. Methods: One hundred RA patients were enrolled in the study. Bilateral US examination of metatarsophalangeal (MTP) joints, proximal interphalangeal (PIP) joints, midfoot joints (talonavicular, calcaneo-cuboid, medial, intermediate and lateral navicularcuneiform and cuneiform-metatarsal joints and cuboid-4th and 5th metatarsal joints) were examined for synovitis and erosion. In addition the plantar fascia and the insertion of the anterior and posterior tibialis and peroneous brevis tendons were imaged. Results: Effusion with synovial proliferation was visualised only at MTP joints in 84 out of 200 (42%) feet, at MTP plus at least one joint of the midfoot in other 41 out of 200 (20%) feet (making a total of 125 out of 200 (62%) MTP joints) exclusively in one or more joints of the midfoot in 7 out 200 (3%) feet, in the PIP joint of the 2nd and 3rd toes in 3 (1.5%) and 4 (2%) feet respectively, while no effusion with synovial proliferation was visualised in the PIP joint of the 4th and 5th toes. Synovitis was present most frequently in the 2nd MTP joint whilst erosions were most frequently imaged in the 5th MTP joint. Conclusion: US examination appears to be a useful imaging technique to study joint and tendon involvement of the foot in RA patients. Moreover, US examination of the foot is more sensitive than clinical examination in the detection of joint inflammation and allows for a better understanding of the features and the progression of the disease. © Clinical and Experimental Rheumatology 2011.

The aims of our study were to investigate the prevalence of ultrasound (US) pathologic abnormalities and to compare them with the clinical findings in the knee of rheumatoid arthritis (RA) patients. One hundred RA patients were enrolled in the study. Bilateral US examination of the knee was performed to visualise the presence of effusion, synovial proliferation, bone erosions, femoral cartilage abnormalities, quadricipital and/or patellar enthesopathy. The popliteal fossa and the calf region were also evacuate to detect popliteal cyst. We observed joint effusion in 140 out of 200 (70%) knees. Synovial hypertrophy was present in 115 out of 140 (82%) knees associated with effusion and in 22 out of 115 (19%) knees intra-articular power Doppler (PD) signal was found. Hyperechoic spots within the cartilage layer, suggestive of pyrophosphate crystals deposit, were detected in the knees of 3 patients. US signs of quadricipital and/or patellar enthesopathy were detected in 53 out 200 (26%) knees. Bone erosions were visualised in 16 out 200 (8%) knees. Popliteal cyst was found in 66 out of 200 (33%) joints. US examination of the knee is more sensitive than clinical examination in the detection of joint inflammation and allows for the identification of different patterns of pathologic changes at knee level, including morphostructural changes at both cartilage and tendon level.

Psoriatic arthritis (PsA) is an arthropathy associated to psoriasis, which is part of the spondyloarthropathy family, and which may present with various forms, from mono-oligoarthritis to symmetric polyarthritis mimicking rheumatoid arthritis. In longstanding disease, the symmetric polyarthritis is the most common pattern of PsA, involving small joint of hands, feet, wrists, ankles and, very frequently, knees. Other common features are represented by the inflammation of enthesis and tendons. Ultrasound (US) examinations were performed using a Logiq 9 (General Electric Medical Systems, Milwaukee, WI) equipped with a multifrequency linear probe, working at 10-14 MHz. One-hundred and sixty-six knee joints were investigated in a total of 83 patients. Prior to US assessment, all patients underwent a clinical examination by an expert rheumatologist who recorded the presence/absence of pain, tenderness (detected by palpation and/or active or passive mobilisation of the knee), and knee swelling. Sixty-two (74.7%) knee joints were found clinically involved, while at least one US finding indicative of joint inflammation was obtained in 70 (84.3%) knee joints. In the 59% of the patients we noticed synovial hypertrophy. Enthesitis was present in 39.7% of the subjects studied. This study demonstrated that US detected a higher number of inflamed knee joints and enthesis with respect to clinical assessment in PsA patients.

Objectives. This study aimed to evaluate the usefulness of a systematic musculoskeletal ultrasonographic (US) assessment in the detection of residual disease activity in patients with early RA who achieved clinical remission. Methods. We prospectively studied 106 early RA patients receiving conventional DMARDs according to a disease activity score (DAS)-steered therapeutic protocol over a 24-month period. Standard evaluation included clinical, laboratory, functional and systematic (44 joints) US assessment. US indexes of grey scale (GS) and power Doppler (PD) synovitis were correlated with clinical evaluation, laboratory indexes and clinical outcome. Clinical remission was defined when DAS was < 1 .6 at two consecutive visits 3 months apart. Results. US examination was significantly more sensitive than clinical examination, both in active disease and in remission. In patients with an active disease, both clinical and US indexes correlated with CRP, whereas in remission only PD still remained significantly correlated. In clinical remission, 95% of the patients showed residual GS synovitis, and 41% of them showed a positive PD signal. Positive PD signal, even in a single joint, resulted the main predictor of relapse within 6 months, both in univariable and multivariable logistic regression analysis. Conclusions. In a cohort of early RA patients treated with conventional DMARDs, US-GS can detect residual disease activity more sensitively than clinical examination both in active disease and in remission. Moreover, PD-positive synovial hypertrophy identifies an ongoing inflammation even during remission and predicts short-term relapse.

Objective. To compare clinical evaluation and ultrasonography (US) in the assessment of joint synovitis in children with juvenile idiopathic arthritis (JIA). Methods. Thirty-two patients underwent clinical evaluation of 52 joints by 2 pediatric rheumatologists. Joints were assessed for swelling, tenderness/pain on motion, and restricted motion. The same joints were scanned independently by an experienced sonographer for synovial hyperplasia, joint effusion, and power Doppler (PD) signal. Results. In total, 1,664 joints were assessed both clinically and with US. On clinical examination, 98 joints (5.9%) were swollen, 59 joints (3.5%) were tender, and 40 joints (2.4%) had restricted motion. On US evaluation, 125 joints (7.5%) had synovial hyperplasia, 153 joints (9.2%) had joint effusion, and 53 joints (3.2%) had PD signal. A total of 104 (6.3%) and 167 (10%) joints had clinical and US synovitis, respectively. Of the 1,560 clinically normal joints, 86 (5.5%) had subclinical synovitis (i.e., had synovitis on US). US led to classifying 5 patients as having polyarthritis who were classified as having oligoarthritis or were found to have no synovitis on clinical evaluation. US variables were moderately correlated with clinical measures of joint swelling, but poorly correlated with those of joint tenderness/pain on motion and restricted motion. Overall, correlations were lower for PD signal than for synovial hyperplasia and joint effusion. Conclusion. We found that subclinical synovitis as detected by US is common in children with JIA. This finding may have important implications for patient classification and may affect the choice of the optimal therapeutic strategy in individual patients.