Ewa Bertolini

Imbalance between HAT and HDAC Activities in the PBMCs of Patients with Ankylosing Spondylitis or Rheumatoid Arthritis and Influence of HDAC Inhibitors on TNF Alpha Production

Objective Acetylation or deacetylation of histone proteins may modulate cytokine gene transcription such as TNF alpha (TNF). We evaluated the balance between histone deacetytlase (HDAC) and histone acetyltransferase (HAT) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) compared to healthy controls (HC) and determined the influence of HDAC inhibitors (trichostatin A -TSA- or Sirtinol -Sirt-) on these enzymatic activities and on the PBMC production of TNF. Methods 52 patients with RA, 21 with AS and 38 HC were evaluated. HAT and HDAC activities were measured on nuclear extracts from PBMC using colorimetric assays. Enzymatic activities were determined prior to and after ex vivo treatment of PBMC by TSA or Sirt. TNF levels were evaluated in PBMC culture supernatants in the absence or presence of TSA or Sirt. Results HAT and HDAC activities were significantly reduced in AS, while these activities reached similar levels in RA and HC. Ex vivo treatment of PBMC by HDACi tended to decrease HDAC expression in HC, but Sirt significantly reduced HAT in RA. TNF production by PBMC was significantly down-regulated by Sirt in HC and AS patients. Conclusion HAT and HDAC were disturbed in AS while no major changes were found in RA. HDACi may modulate HDAC and HAT PBMC expression, especially Sirt in RA. Sirtinol was able to down regulate TNF production by PBMC in HC and AS. An imbalance between HAT and HDAC activities might provide the rationale for the development of HDACi in the therapeutic approach to inflammatory rheumatic diseases.

Septic arthritis of the acromioclavicular joint

The acromioclavicular joint is rarely the site of septic arthritis. We conducted a retrospective review at our rheumatology department, which identified five cases within the last 6 years. All five patients were males, and their mean age was 63 years. Risk factors were consistently identified and included intravenous substance abuse, prior joint disease, a recent history of intraarticular injections, and a remote history of surgery. Joint aspiration was performed in all five patients and provided the organism in two patients. Blood cultures recovered Staphylococcus aureus in three patients, a coagulase-negative Staphylococcus in one patient, and no organism in one patient. Ultrasonography and/or magnetic resonance imaging established the early diagnosis in four patients and ruled out concomitant involvement of the glenohumeral joint. Only about 20 cases of septic arthritis of the acromioclavicular joint have been reported to date. This rare infection must be diagnosed rapidly to prevent joint destruction. The treatment is that usually recommended for septic arthritis.

Rheumatoid arthritis and aromatase inhibitors

Aromatase inhibitors are widely used for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. Joint pain is a common side effect. We report three cases of rheumatoid arthritis with onset after the initiation of aromatase inhibitor therapy. All three patients had antibodies to cyclic citrullinated peptides and two had sicca syndrome. Few similar cases have been published. Although a chance occurrence cannot be ruled out, evidence from animal models suggests that aromatase inhibitors may trigger or reveal rheumatoid arthritis.

Vertebral osteitis adjacent to kyphoplasty.

Vertebroplasty and vertebral kyphoplasty are increasingly performed to treat vertebral fractures, most notably those related to osteoporosis. Adverse effects are uncommon and consist chiefly of cement leakage out of the vertebral body and of vertebral fractures adjacent to the treatment site. We report two cases of vertebral osteitis adjacent to vertebroplasty sites, in a 60-year-old woman and a 79-year-old man. Kyphoplasty to treat an osteoporotic vertebral fracture was followed by acute pain with an inflammatory time pattern and laboratory evidence of inflammation. Time to symptom onset was 10 days and 45 days, respectively. Magnetic resonance imaging showed changes consistent with inflammation in an adjacent vertebra (low signal on T1 images, gadolinium enhancement, and high signal on T2 images). A biopsy of the lesion disclosed moderate nonspecific inflammation, with no microorganisms or evidence of malignancy. Both patients recovered slowly. The male patient experienced a fracture at the site of the lesion. Few cases of osteitis adjacent to kyphoplasty have been reported. The underlying pathophysiology may involve changes in vertebral loading and cement leakage into the intervertebral disk.

Histone deacetylase inhibitors: New treatment options for inflammatory joint disease? ☆

Histone deacetylase inhibitors (HDIs) are a new class of compounds that are being developed for the treatment of malignancies such as cutaneous T-cell lymphoma. HDIs inhibit the removal of acetyl groups from histones. The histone acetylation process is dependent on two enzymes, histone acetyl transferase (HAT) and histone deacetylase (HDAC), and regulates the expression of genes, including those encoding cell survival or apoptosis. In addition to regulating cell growth, HDIs exert anti-inflammatory effects by controlling the production of anti-inflammatory cytokines; modulating the function of cells such as T cells, monocytes-macrophages, chondrocytes, and osteoclasts; and modulating angiogenesis. In several animal models of arthritis, HDIs improve the clinical manifestations and prevent damage to the bone and cartilage. In humans, the only relevant data available so far come from studies of HAT and HDAC expression in the synovial membrane of patients with rheumatoid arthritis. HDIs may hold promise for the treatment of inflammatory joint disease.

Peripheral Blood B cell Subsets and BAFF/APRIL Levels and their Receptors are Disturbed in Rheumatoid Arthritis but not in Ankylosing Spondylitis

Background: To evaluate the distribution of circulating B cell subsets and their expression of BAFF/APRIL receptors (BAFF-R, TACI and BCMA) as well as circulating levels of BAFF and APRIL in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) compared to healthy controls (HC).Methods: 59 patients with RA, 61 patients with AS and 61 HC were evaluated. All patients were receiving traditional treatments and had not received prior biological treatment. Peripheral blood B cell subsets were assessed using multicolor flow cytometry using CD27, CD38 and IgD staining. Expression of BAFF-R, TACI and BCMA was analyzed on each cell subset.Results: Distribution of peripheral B cells subsets was disturbed in RA compared to HC, with a decreased proportion of naive and transitional B cells (p<0.005), whereas B cell subsets were comparable between AS and HC. Circulating BAFF did not differ between the three groups, while the ratio of BAFF/B cell number was significantly higher in RA compared to HC (p<0.001). Circulating APRIL levels were increased in RA compared to HC (p<0.001). Circulating BAFF and APRIL, and BAFF/B cell ratio did not differ between AS and HC. We also observed increased expression of BCMA, but not BAFF-R in RA, on both naive and memory B cell subsets (post germinal center) (p<0.005), whereas TACI expression was decreased on memory B cells (p=0.001). The expression of BAFF/APRIL receptors did not differ between AS and HC.Conclusion: Disturbances in B cell homeostasis in RA may promote B cell survival and deregulation, favoring the emergence of autoimmune B cells. Conversely, B cell homeostasis is not disrupted in AS.

Management of ankylosing spondylitis with infliximab

Ankylosing spondylitis (AS) is a systemic inflammatory rheumatic disease responsible for back pain, stiffness and progressive loss of functional capacity with limited therapeutic options. Regular physical exercises together with the use of nonsteroidal antiinflammatory drugs are the two recognized treatment options in AS. Infliximab is a chimeric anti-tumor necrosis factor-α monoclonal antibody that has been demonstrated to be highly effective in the treatment of AS, providing clinical amelioration at both axial and peripheral skeleton. Infliximab also improves quality of life, function, biological parameters (acute phase reactants) and inflammatory lesions of the spine as detected by magnetic resonance imaging. It is given at a 5 mg/kg dosage, as an infusion at weeks 0, 2, 6, and every 6 to 8 weeks after. Open-label and placebo-controlled trials have well demonstrated its high level of efficacy, with an improvement of the disease activity of at least 50% in 60%–80% of patients. In a large placebo-controlled trial, Assessment in Ankylosing Spondylitis Response Criteria (ASAS20) responders were observed in 61.2% of patients receiving infliximab compared to 19.2% of patients under placebo. Long-term efficacy is maintained when infliximab is administered every 6–8 weeks. Consensus international guidelines for the initiation and the use of this expensive treatment are available. Some questions remain, including the long-term safety, in particular the risk of lymphoma, and the potential influence of infliximab on radiological progression which is not currently demonstrated. Despite these concerns, infliximab has revolutionized the management of AS and represents a considerable therapeutic advancement in this disabling disease.

Compression of the common peroneal nerve due to peroneal muscle infarction in a patient with diabetes

Joint Bone Spine - In Press.Proof corrected by the author Available online since samedi 21 juillet 2018