Occult HBV infection may negatively impact on drug survival in patients with rheumatoid arthritis on treatment with a first biologic drug. An appraisal from the Biologic Apulian Registry (BIOPURE).

We performed a retrospective analysis to evaluate the survival on first line biologic drug of rheumatoid arthritis (RA) patients with potential occult HBV infection (pOBI). We analysed longitudinal data of 486 consecutive RA patients starting a first biological drug in a time frame from 1st January 2008 to 31st December 2014. Demographic and disease related characteristics were collected at baseline and at the last observation visit. Baseline serological markers of HBV infection and causes of treatment discontinuation were also recorded. Primary endpoint was the influence of pOBI on drug survival, estimated by Kaplan-Meier life table analysis. Estimates hazard ratios (HRs) of drug discontinuation, adjusted for disease characteristics, biological drug class and HBcAb status were computed by Cox-regression models. The retention rate was significantly lower in pOBI positive patients (58.2%) when compared to pOBI negative ones (67.8%) and this data was confirmed also when only discontinuation due to ineffectiveness was considered (pOBI positive 66.4% vs pOBI negative 75.3%, long rank 7.93, p=0.005). Cox regression models showed a significant association between HBcAb-neg (HR 0.58, 0.41-0.84), higher ESR-DAS28 at baseline (HR 1.07, 1.03-1.11) or RF/ACPA-neg (HR 1.46, 1.04-2.06) and drug discontinuation. Occult HBV infection seems to influence negatively the effectiveness of biological therapies in RA patients.

Varicella-zoster virus infection in rheumatoid arthritis patients in the anti-tumour necrosis factor era.

Patients with rheumatoid arthritis are increasingly being treated with different drugs (both non-biologic and biologic disease-modifying anti-rheumatic drugs - DMARDs) that may have immunomodulatory, cytotoxic, or immunosuppressive effects; in particular, anti-tumour necrosis factor (TNF) agents are raising major concern as regards safety issues. An increased risk of infections has been extensively reported during anti-TNF treatment, owing to the primary role of TNF in host defense and immune responses. Although in clinical practice cases of reactivation of varicella zoster virus (VZV) infections during therapy with TNF inhibitors commonly occur, the knowledge on this topic deriving from randomised clinical trials is limited. In this narrative review we focus on the pathophysiology of VZV infection and the role of TNF, and report the available data about VZV outbreaks recorded on Registries of rheumatic patients treated with anti-TNF agents. Finally, we discuss screening strategies and promising preventive measures against VZV infection.

Chondrocyte phenotyping in human osteoarthritis.

Cell-ECM (extracellular matrix) interactions are believed to play a key role in maintaining the normal structure of tissues such as cartilage. Cell surface adhesion molecules have been reported to mediate chondrocyte binding to ECM proteins in human normal cartilage but the behaviour of these molecules in human osteoarthritic cartilage is unknown. We studied receptor matrix proteins on freshly isolated chondrocytes obtained from 10 patients with osteoarthritis (OA). Chondrocytes were isolated by enzymatic digestion from three zones of the articular cartilage with a different degree of macroscopic and microscopic damage and chondrocyte phenotype was defined by flow cytometry. Chondrocytes strongly expressed beta1, integrin but not beta3 integrin. LFA-1 (CD18/CD11a) and ICAM-1 (CD54) antigens were almost undetectable. Interestingly, beta1 expression was significantly higher in the minimally damaged zone than in the zones with medium and maximum damage. These data show that beta1-integrin-mediated chondrocyte-ECM interactions decrease in osteoarthritic cartilage suggesting that perturbations of chondrocyte-matrix signalling occurs during OA.

Integrin expression on chondrocytes: correlations with the degree of cartilage damage in human osteoarthritis.

OBJECTIVE: To verify the distribution of different types of beta 1 integrin on the plasma membrane of chondrocytes and to correlate the pattern of integrin expression to the severity of osteoarthritis (OA). METHODS: The articular cartilage of ten OA patients who had undergone surgical knee replacement for "genu varum" were studied. The cartilage was separated into three zones that macroscopically and microscopically showed a decreasing degree of anatomic lesions. After enzymatic digestion, the isolated chondrocytes were immediately challenged with monoclonal antibodies against the beta 1, alpha 1-6 and alpha v chains. The phenotypic study was paralleled by a cell cycle analysis performed by flow cytometry on chondrocytes stained with propidium iodide. RESULTS: Chondrocytes isolated from the articular cartilage of osteoarthritic patients expressed, in different percentages, all the alpha chains (alpha 1-6 and alpha v) of the beta 1 integrins. The alpha chain most frequently expressed was alpha 1, followed by alpha 3, alpha 5, alpha 2 and alpha v, with lesser amounts of alpha 4 and alpha 6. The beta 1 chain was expressed (on average) on the 40% of the chondrocytes regardless of the zone they were isolated from. Differential phenotypic analysis of the three zones showed that beta 1 integrins correlate inversely with the severity of the anatomic lesions and the cycle phase of the chondrocytes (the G0/G1 phase prevailed in the anatomically normal cartilage of the least damaged zone, and the S-phase in the most damaged zone). CONCLUSIONS: This study provides evidence of the existence of beta 1 integrins on the surface of chondrocytes from human OA cartilage, all of the alpha chains being represented, although in different percentages. Moreover, an inverse correlation was demonstrated between the severity of the anatomical changes found in the zones and the phenotypic/metabolic changes of the cells. These results, together with the well known inside-out signaling function of the adhesion molecules, highlight the key role of matrix interactions in the pathogenesis of the anatomic changes in OA.

Recovery of erosive rheumatoid arthritis after human immunodeficiency virus-1 infection and hemiplegia.

The effects of human immunodeficiency virus type-1 (HIV-1) infection on rheumatoid arthritis (RA) are a matter of debate as there is no agreement on the influence of HIV-1 related immunodeficiency on this disease. We describe a patient with RA with symmetric joint erosions and positive rheumatoid factor (RF) who developed classic acquired immunodeficiency syndrome (AIDS) followed by left hemiplegia. RA improved with resolution of bony erosions and disappearance of RF, and reached complete clinical remission only in the paralytic limbs. Our observation suggests that, although essential, cell mediated immune response is not the sole mechanism involved in RA pathogenesis. Other factors such as the nervous system may play an important role.

The effect of essential fatty acid supplementation on keratinocyte replication.

Epidermal cell growth in culture, using the low calcium, low serum technique described by Boyce, is thought to induce rapid expansion by inducing an essential fatty acid (EFA) deficiency state. To determine the mechanisms whereby EFA deficiency induces increased epidermal cell growth, keratinocytes were passaged into medium without or with the addition of EFAs, 18:2(n-6), 20:4(n-6). The resulting populations were assayed for replication rate, differentiation, and plating efficiency. Supplemental EFAs significantly decrease keratinocyte culture expansion. This is evidenced by an increase in generation time, a decrease in thymidine incorporation, and a decrease in modeled replication rate. EFA supplementation also increased the expression of cornified cell envelopes. Serum-free medium induces EFA deficient keratinocytes that demonstrate increased replication and decreased differentiation. Restoration of EFAs reverses these changes. It may be possible to manipulate keratinocyte physiology using fatty acid modifications.

Expression of membrane-bound peptidases (CD10 and CD26) on human articular chondrocytes. Possible role of neuropeptidases in the pathogenesis of osteoarthritis.

OBJECTIVE: To evaluate the cell surface expression of cell membrane-bound peptidases CD10 and CD26 on osteoarthritic (OA) chondrocytes, correlating it with the cell cycle phase and with the severity of OA lesions found in different load zones of the cartilage from human knees. METHODS: Chondrocytes freshly isolated from three different load zones of cartilage, obtained from 10 OA patients undergoing surgical knee replacement, were analyzed for the expression of CD10 and CD26 and for their cell cycle phase by flow cytometry. Statistical analysis was carried out using the multifactorial analysis of the variance with the LSD (least square difference) range test. The Chi square test was used to compare the cell cycle phases. RESULTS: Analysis of the chondrocyte cell cycle showed a significantly high proportion of cells in the S-phase in the maximum load zone in comparison with the minimum load zone (p < 0.001); the percentage of resting cells (G0/G1 phase) was significantly higher in the minimum load zone than in the maximum load zone (p < 0.001). The expression of CD10 and CD26 on chondrocytes was significantly reduced in the maximum load zone of the cartilage and was directly related to the progressive worsening of osteoarthritic lesions. CONCLUSIONS: These data demonstrate, for the first time, that articular chondrocytes express on their surface CD10 and CD26 peptidases. Neprilysin 3.4.24.11 (CD10) and dipeptidyl peptidase IV 3.4.14.15 (CD26) have been shown to play a specific role in the control of growth and differentiation of many cell types by cleaving growth factors able to promote cellular proliferation. Our results indicate that CD10 and CD26 are down-regulated in the maximum load zone of the knee OA cartilage: this condition may allow the increase of local levels of growth factors causing chondrocyte activation. Furthermore, as CD26 mediates cell binding to fibronectin and collagen, its reduction in osteoarthritic cartilage may reflect a perturbation of chondrocyte interactions with the extracellular matrix.

The effects of burn blister fluid on keratinocyte replication and differentiation.

The optimal clinical care of burn blisters has not been determined. The effects of burn blister fluid and control serum on epidermal cell proliferation and differentiation were determined. Both burn blister fluid and serum decreased the cell responses necessary for healing of the burn wound by approximately 40%. The degree of suppression varied from 81% to 28% dependency on the specific burn blister fluid and cell tested. These data suggest that reepithelialization may be inhibited beneath burn blisters. We conclude that in most cases burn blisters should be debrided.