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Background and Aims: Rheumatic manifestations are frequent in inflammatory bowel disease (IBD) and are associated with a wide range of clinical patterns., Methods: Articular symptoms and signs were investigated by questionnaire in a cohort of 651 pts, mean age 42+/-14 years, followed at two referral hospitals over a 12-month period., Results: 142 ulcerative colitis (UC) and 120 Crohn's disease (CD) patients referred articular pain during their IBD history: in 46% this was associated with active IBD, in 56% symptoms were intermittent and in 19% symptoms preceded IBD diagnosis. 62 pts (28 UC, 34 CD) complaining of articular symptoms at the time of the interview, were investigated by the rheumatologist: arthropathy was axial in 52%, oligoarticular in 16% and polyarticular in 23%. Oligoarthritis commonly involved the lower limbs and was more commonly associated with UC. The mean number of small joints involved was significantly higher in CD than in UC pts (9.9+/-8.2 vs. 5.6+/-4.3; p<0.01). Bone scintigraphy was abnormal in 70% of pts., Conclusions: Prevalence of self-reported articular symptoms in IBD patients exceeds 40% with 9.5% incidence during 1-year follow up. Symptoms predict entheropatic involvement of the locomotor system.

Blau syndrome (BS) is a rare familial disease transmitted as an autosomal dominant trait, characterized by arthritis, uveitis, skin rash and granulomatous inflammation. Until now BS has been observed in 136 persons belonging to 28 families as well as in 4 sporadic cases. The gene responsible for BS has recently been identified in the nucleotide-binding domain (NBD) of caspase recruitment domain (CARD15/NOD2), also involved in the pathogenesis of Crohn's disease. In addition to three missense mutations (R334Q, R334W and L469F) previously identified, a new CARD 15 mutation (E383K) has recently been described in a family followed by us for the past 25 years. The characteristics of this family which, to our knowledge, is the only one affected with BS in Italy, are the object of this manuscript. Both the proband and her daughter were originally affected with a papulonodular skin eruption and then with mild arthritis of the hands and feet. The proband, but not the daughter, complained of severe chronic bilateral uveitis, followed by glaucoma and, a few years later, by cataracts. Histological examination of skin biopsies from both subjects and a joint biopsy (daughter only), showed non-caseating granulomas with multinucleated giant cells which, at electron microscopy, revealed "comma-shaped bodies" in epithelioid cells, thought to be a marker for BS. The disease is presently well controlled with low doses of prednisone for the mother and non-steroidal anti-inflammatory drugs (NSAIDs) plus low doses of prednisone, when necessary, for the daughter. As in Crohn's disease, CARD15/NOD2 mutation is believed to be responsible for the granulomatous autoinflammatory reactions probably triggered by microorganisms in BS.

Objectives: The objective of this study was to evaluate the effects and the tolerability of mud packs and thermal baths in a group of patients affected with this disease., Methods: Twenty-four patients with spondylitis and Crohn's disease or ulcerative colitis, treated with 5-ASA or sulfasalazine, were randomised and assessed by an investigator independent from the spa staff: 12 were submitted to a cycle of mud-bath treatment (12 mud packs and 12 thermal baths over a period of two weeks) and 12 were enrolled as controls. Patients were evaluated by BASDAI, BASFI, BAS-G and VAS for back pain before, at the end of a cycle of mud-bath treatment, and after 12 and 24 weeks. C reactive protein serum levels detected by high sensitivity nephelometric method and gut symptoms evaluated by CDAI or Powell-Tuck index were assessed at the same time periods., Results: A significant reduction of clinical evaluation indices of spondylitis was observed at the end of the cycle of mud-bath treatment. BASDAI50 improvement remained significant until the end of the follow-up (24 weeks). C reactive protein serum levels didn't show significant changes. No patient referred any gut symptom exacerbation. No significant changes in clinical evaluation indices, in IBD activity indices and in CRP serum levels were observed in the control group., Conclusion: Mud-bath treatment in patients with spondylitis associated with inflammatory bowel disease is well tolerated and may improve spinal symptoms and function for several months.

The classical definition of psoriatic arthritis (PsA) as an inflammatory arthritis associated with psoriasis reflects only in part the large spectrum of musculoskeletal disorders found in patients with psoriasis. In particular, enthesopathy, dactilytis, osteitis and axial involvement are frequently neglected and probably account for the unsatisfactory response of PsA to traditional drugs, such as NSAIDs, steroids and DMARDs. Furthermore, these drugs showed only a partial ability to influence radiographic progression and psoriasis. The new anti-TNF agents, in particular etanercept but also infliximab and adalimumab, have demonstrated a comprehensive effectiveness on the multiple aspects of the PsA disease, including quality of life and slowing of radiographic progression. Despite this clear efficacy, the actual mechanisms by which TNF-blocking agents are able to obtain all these effects are still incompletely understood. However, the success of this therapy suggested one of the best ways for further research in the field of PsA. In this new fashion, the most stimulating hypotheses involving TNF are those regarding genetic predisposition, angiogenesis and osteoclastogenesis.

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.

Objective: We evaluated the induction and clinical significance of ANA, anti-dsDNA and anti-ENA during infliximab therapy in patients with Rheumatoid Arthritis (RA) or Ankylosing Spondylitis (AS)., Methods: We tested sera from 30 RA and 30 AS patients before and during treatment with infliximab. ANA and antidsDNA were determined by indirect immunofluorescence and anti-ENA by an "in house" counterimmunoelectrophoresis. Statistical analysis was performed by X2 and McNemar's tests and U-test of Mann-Whitney., Results: Eight of the 30 RA patients and 1 of the 30 AS patients were positive for ANA before treatment with infliximab. Eighteen of the 22 (81.8%) negative patients with RA and 11 of the 29 (37.9%) negative patients with AS became positive for ANA during infliximab treatment. No ANA positive patients became negative during the therapy. The difference between ANA before and after treatment resulted significant in both RA and AS patients (p=0.001). The frequency of anti-dsDNA and anti-ENA did not change significantly from baseline, in both RA and AS patients. Acquired ANA positivity was not associated with clinical signs of lupus syndrome and was not correlated with adverse events. The mean values of ESR and CRP in RA patients who became positive for ANA were significantly decreased (p=0.01 and p=0.02 respectively)., Conclusions: Infliximab treatment induced a significant increase in the frequency of ANA in RA and AS patients. The significance of ANA development in these diseases is at present unknown. The significant decrease of ESR and CRP in RA patients who became positive for ANA after treatment should be investigated in a larger number of patients.

The autoinflammatory disorders are a new and expanding classification of inflammatory diseases characterized by recurrent episodes of systemic inflammation in the absence of pathogens, autoantibodies or antigen specific T cells. These disorders are caused by primary dysfunction of the innate immune system, without evidence of adaptive immune dysregulation. Innate immune abnormalities include aberrant responses to pathogen associated molecular patterns (PAMPs) like lipopolysaccharide and peptidoglycan, prominent neutrophilia in blood and tissues, and dysregulation of inflammatory cytokines (IL-1beta, TNF-alpha) or their receptors. The autoinflammatory diseases comprise both hereditary (Familial Mediterranean Fever, FMF; Mevalonate Kinase Deficiency, MKD; TNF Receptor Associated Periodic Syndrome, TRAPS; Cryopyrin Associated Periodic Syndrome, CAPS; Blau syndrome; Pyogenic sterile Arthritis, Pyoderma gangrenosum and Acne syndrome, PAPA; Chronic Recurrent Multifocal Osteomyelitis, CRMO) and multifactorial (Crohn's and Behçet's diseases) disorders. Mutations responsible for FMF, TRAPS, CAPS, PAPA are in proteins involved in modulation of inflammation and apoptosis.

Arthritis and tenosynovitis are frequently reported as complications of inflammatory bowel diseases. About 10% of patients with ulcerative colitis presents articular inflammation, usually in the phases of activity of intestinal disease. Tenosynovitis is also a frequent complication of ulcerative colitis. We describe here a case of tenosynovitis of both ankles occurring in a patient affected by ulcerative colitis not in active phase. Chest X-ray and TC showed hilar lymph node enlargement and transbronchial biopsy confirmed the diagnosis of sarcoidosis. In this disease tenosynovitis is very rare, unlike arthritis that is rather common. In conclusion we observed a case of ankle bilateral tenosynovitis as onset manifestation of sarcoidosis.

The caspase recruitment domain gene CARD15/NOD2, encoding a cellular receptor involved in an NF-kappaB-mediated pathway of innate immunity, was first identified as a major susceptibility gene for Crohn's disease (CD), and more recently, as responsible for Blau syndrome (BS), a rare autosomal-dominant trait characterized by arthritis, uveitis, skin rash and granulomatous inflammation. While CARD15 variants associated with CD are located within or near the C-terminal leucine-rich repeat domain and cause decreased NF-kappaB activation, BS mutations affect the central nucleotide-binding NACHT domain and result in increased NF-kappaB activation. In an Italian family with BS, we detected a novel mutation E383K, whose pathogenicity is strongly supported by cosegregation with the disease in the family and absence in controls, and by the evolutionary conservation and structural role of the affected glutamate close to the Walker B motif of the nucleotide-binding site in the NACHT domain. Interestingly, substitutions at corresponding positions in another NACHT family member cause similar autoinflammatory phenotypes.

Objective: Disruption of intestinal barrier function, followed by increased antigen load, may possibly trigger joint inflammation. In seronegative spondyloarthritis (SpA) both gut inflammation and altered intestinal permeability have been reported. We evaluated the influence of Helicobacter pylori and nonsteroidal antiinflammatory drugs (NSAID) on gastrointestinal (GI) permeability in SpA. Twenty SpA patients (7 women, mean age 47 +/- 13 SD yrs), 30 patients with endoscopic gastritis (EndG; 17 women, mean age 48 +/- 14 yrs), and 35 healthy controls (16 women, mean age 40 +/- 15 yrs) were studied. No patient was undergoing antisecretory therapy. In the SpA group, 8 patients were chronically taking NSAID and 12 took NSAID occasionally, none during the month before the study. All subjects were assessed for gastroduodenal (sucrose) and intestinal (lactulose/mannitol) permeability test and H. pylori status (urea breath test)., Results: H. pylori affected GI permeability in both SpA and EndG patients. After eradication therapy, sucrose excretion remained increased in SpA and reverted to normal in EndG patients, whereas lactulose/mannitol test became comparable to controls in both groups. SpA patients taking chronic NSAID had increased gastroduodenal permeability only when H. pylori-positive. In SpA patients, GI permeability did not correlate with clinical activity or biochemical inflammation., Conclusion: In SpA, H. pylori and NSAID contribute to impaired GI permeability. Eradication therapy may help to maintain epithelial barrier function and possibly influence clinical improvement in patients with SpA.

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.

Inflammatory bowel diseases (IBD), as Crohn's disease (CD) or ulcerative colitis (UC), are frequently complicated by joint complaints with prevalence that varies between 10 and 28%. The IBD related arthropathy may be expressed as peripheral arthritis or axial one frequently indistinguishable from the classical ankylosing spondylitis (AS). According to ESSG criteria for spondyloarthropathy, the presence of synovitis or the inflammatory back pain (IBP) in IBD patients is diagnostic for spondyloarthropathy, but for diagnosis of ankylosing spondylitis also radiological criteria must be fulfilled. There are few studies regarding the radiological prevalence of sacroiliitis in patients with IBD. We examined, by plain film radiograms of pelvis, 100 sacroiliac joints (SJ) of 50 IBD patients with IBP. The New York (1984) SJ radiological score with gradation from 0 to 4 was applied. Total sacroiliac score (SJS) was summarized between left and right side (from 0 to 8). Fourteen patients fulfilled New York modified criteria for AS and 8 patients had unilateral 2nd grade sacroiliitis. Only 4 of 14 AS patients (28%) were HLA B27 positive. Thirty patients had localized IBP, 10 extended to buttock and 4 extended to sacrum. Sixteen patients had sciatica-like extension of back pain. A difference in SJS between left and right side was observed only in CD patients (1.3 +/- 0.8 and 0.8 +/- 0.9 respectively; p < 0.05), but not in UC (1.5 +/- 1.2 vs 1.5 +/- 1.3; p = ns) nor in total IBD patients (1.4 +/- 1.0 vs 1.2 +/- 1.2; p = ns). Total SJS was higher in UC respect CD, but not significantly (2.9 +/- 2.3 vs 2.1 +/- 1.5; p = ns). Our data confirm the importance of these symptoms in patients with IBD, who need to be carefully investigated also for these aspects.

Preiser's syndrome is a rare osteochondrosis affecting the carpal scaphoid, frequently related with an avascular necrosis. Osteoarthritic changes of the articular cartilage, local synovitis, and loose fragments are the most common findings associated with this syndrome. We report here two patients with Preiser's syndrome, one with and one without a traumatic history, both presenting with pain, swelling and functional impairment of the wrist. In one patient radiography was sufficient for the diagnosis, in the other NMR was necessary to clearly establish type and extension of the lesion. Differential diagnosis may be sometimes difficult and the therapeutic approach depends on several aspects, including etiology and type of occupational activity.

The frequency of pericardial involvement in Systemic Sclerosis (SSc) is high on autoptic or echocardiographic studies, but the clinical recognition of pericarditis with or without effusion is rare. We describe a case of a 71-year-old female with no previous history of heart disease, who presented with a large pericardial effusion and tamponade that required pericardial drain. She had suffered from Raynaud's phenomenon since 25 years. Six weeks after hospital discharge she complained of skin hardening on left leg. Pericardial tamponade is a very rare manifestation of SSc and occurs both early or late in the course of the disease, but in our case it preceded the recognition of scleroderma. We have only identified two other cases of pericardial effusion preceding cutaneous involvement in scleroderma.