Marta Podswiadek

A new CARD15 mutation in Blau syndrome

The caspase recruitment domain gene CARD15/NOD2, encoding a cellular receptor involved in an NF-κB-mediated pathway of innate immunity, was first identified as a major susceptibility gene for Crohns 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-κB activation, BS mutations affect the central nucleotide-binding NACHT domain and result in increased NF-κB 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.

YKL-40 as a Marker of Joint Involvement in Inflammatory Bowel Disease

Rheumatic symptoms are the most common extra-intestinal manifestations of inflammatory bowel diseases (IBD). Both ulcerative colitis and Crohn disease (1)(2) can be complicated by seronegative spondyloarthropathies, including two principal patterns of arthritis: spondylitis and peripheral arthritis. Spondyloarthropathies resembling idiopathic ankylosing spondylitis occur in 10% of patients with ulcerative colitis and, less frequently, in those with Crohn disease; peripheral, often asymmetric, arthropathies occur in 5–20% of IBD patients. Unlike arthropathy limited to five or fewer joints, polyarthropathy and spondyloarthropathies do not reflect the activity of the underlying IBD. The “gold standard” for assessing joint damage remains the plain radiograph, which images only the bone and allows reliable detection of changes within a time span of at least 12 months. Importantly, all such techniques image only damage that has already occurred. Even after repeated investigations, they are of limited use in informing the clinician of continuing or future damage. Biochemical markers may provide a valuable tool for the frequent quantitative measurements required for the diagnosis and monitoring of joint disease. Highly sensitive C-reactive protein (CRP) assays provide information on the inflammatory process (3) but are poor markers for joint disease in IBD. Other markers for joint disease have been proposed (4) that are related to structures within joints. The concentrations of YKL-40 in serum and synovial fluid are closely correlated in patients with joint disease (5), suggesting that most of the protein found in serum may be produced within the joint (6)(7). YKL-40 is produced not only by chondrocytes and synovial cells but also by macrophages, neutrophils, cancer cells, endothelial cells, smooth muscle cells in blood vessels, and by cells (probably hepatic stellate cells) in the fibrotic liver (8)(9)(10)(11)(12)(13). The protein is a growth factor for fibroblasts, chondrocytes, …

Rheumatic Manifestations Associated with Inflammatory Bowel Diseases

Rheumatic manifestations, in particular joint complaints, are frequent features in inflammatory bowel disease (IBD), with a prevalence varying from 10 to 35%. Their spectrum is almost wide, involving bone, tendons, entheses and joints. Joint manifestations may be seen as arthralgia and/or inflammatory arthropathies. These latter may in turn be found in three principal forms: the peripheral, the axial or spondylitis and that overlapping between these two varieties. Peripheral arthritis may be classified in oligoarticular (type I) and polyarticular (type II) forms. Oligoarthritis is the most frequent. Usually asymmetric, involving large joints of lower limbs, it is transient, commonly associated with IBD flares, and may disappear after few weeks, although in 10% of cases it may evolves to chronic arthritis. Type II arthritis is polyarticular and symmetric, involving hands and feet but also large joints. The prevalence is about 2-4% of IBD patients, its course is independent from IBD flares and usually evolves in chronic disease. Peripheral arthritis is classically nondeforming, non erosive, and seronegative for the rheumatoid factor. Axial involvement is equally frequent in both CD and UC and varies in different studies from 10 to 30% for sacroiliitis and from 3 to 10% for ankylosing spondylitis. Its course is independent from IBD state, the extension of IBD involvement and the occurrence of flares. The treatment of rheumatic manifestations in IBD is frequently problematic, due to the possibility of frequent side effects. Among drugs used for IBD, corticosteroids, also effective in joint complaints, may have osteopenic effects; sulfasalazine, sometimes able to control peripheral arthritis, is ineffective for the axial involvement. A potential gut toxicity is associated with the use of NSAIDs, which in some patients may induce asymptomatic lesions causing small gut bleeding and loss of proteins. Local injections with steroid may be used for tendonitis, monoarthritis or isolated sacroiliac inflammation. In patients with peripheral arthritis, especially when involving several joints and/or refractory to other therapies, disease modifying drugs for rheumatoid arthritis (DMARDs) should be used. Among these, methotrexate is also useful for CD while it seems inefficacious in UC. Cyclosporin, administrated alone or in association, may contain flares of steroid refractory UC. Azathioprine is commonly used to induce and maintain remission in refractory CD while its role on arthritis is marginal. Aminobisphosphonates seem effective for both axial and peripheral involvements and probably, it may represent a good option for the future in the management of enteropathic arthritis, because of their anti-osteopenic effect. Finally, the most promising opportunities derive from the recently introduced biologic agents, in particular anti-tumour necrosis factor (TNF) . Infliximab, a chimeric anti-TNFα monoclonal IgGI antibody, has largely demonstrated its efficacy in refractory CD and in all rheumatic manifestations. Other biologic agents are proposed, including the human anti-TNF monoclonal antibody adalimumab, antibodies to integrins (anti-α 4 β7), anti-ICAM-1 (intracellular adhesion molecule 1) and IL-10. Concerning the surgical options, the colectomy may be protective on type I peripheral arthritis but is not influent on the course of axial disease, while the surgery on small intestine usually do not prevent the appearance of peripheral arthritis. In the case of destructive arthritis, like coxitis, joint prosthesis may be necessary.