Johannes von Kempis

Neuropeptide Y is an inducible gene in the human immune system

This study reports on neuropeptide Y (NPY) mRNA expression in human peripheral blood mononuclear cells (PBMC) and lymphoid tissues. By reverse transcription polymerase chain reaction (RT-PCR) it is shown that activated human PBMC of normal blood donors expressed the NPY gene. The PCR products had the expected size and Northern blotting demonstrated the presence of the 0.8-kb NPY mRNA. To define the subpopulations of mononuclear cells expressing this neuropeptide, purified monocytes, B cells and T cells were stimulated with specific activators. Monocytes and in vitro matured macrophages expressed NPY mRNA in response to phorbol myristate acetate (PMA). B lymphocytes expressed NPY mRNA following stimulation with antibody to surface immunoglobulin and PMA. In order to analyze whether these cell types express NPY under physiological conditions in vivo, human bone marrow, tonsil and thymus were analyzed. In situ hybridization of bone marrow revealed a small number of cells containing high levels of NPY mRNA which was also detected in RNA extracts of human thymus and tonsil. In summary, NPY is an inducible gene in human lymphocytes and monocytes and it is expressed at sites where these cells are activated in vivo.

The nerve growth factor/tumor necrosis factor receptor family

Receptors in the nerve growth factor/tumor necrosis factor receptor family are characterized by the presence of cysteine‐rich motifs of ~40 amino acids in the extracellular domain. The ligands are type II transmembrane proteins with β‐strands that form a jelly‐roll β‐sandwich. The receptors recognize soluble or cell‐surface‐bound ligands and mediate diverse cellular responses. Activation of intracellular signals is mediated at least in part by the association of proteins with a RING finger motif or a death domain to the cytoplasmic domains of the receptors. In addition to cell‐membrane‐bound receptors soluble forms have been described for most of the receptors. Activation of intracellular signals not only occurs through ligand binding to the receptors but cross‐linking of at least some members of the ligand family can regulate cell functions.

Vasculitic complications of interferon-α treatment for chronic hepatitis C virus infection: case report and review of the literature

Chronic infection with hepatitis C virus (HCV) may be complicated by the development of systemic vasculitis. Vasculitis is either caused by mixed cryoglobulinemia or a non-cryoglobulinemic vasculitis resembling polyarteritis nodosa (PAN). Antiviral treatment with interferon-α (IFN) and subsequent clearing of HCV mostly leads to improvement of vasculitic symptoms, but vasculitis may also be exacerbated and even cases of new onset of vasculitis may occur. Exacerbations of both cryoglobulinemic and PAN-type vasculitis in chronic HCV infection have been described under treatment with IFN. The most common symptom is vasculitic neuropathy. However, peripheral neuropathy in a HCV-infected patient treated with IFN may also be caused by direct neurotoxic or antiangiogenic effects of IFN itself, often requiring a nerve biopsy to establish the exact diagnosis. The clinical course of vasculitic complications of IFN treatment is variable and ranges from regression of symptoms despite continuation of IFN treatment to fatal exacerbations despite termination of IFN treatment and additional immunosuppressive therapy. In most cases of IFN-induced vasculitis, immunosuppressive therapy with corticosteroids has been employed, leading to improvement of symptoms. We report the case of a patient with chronic HCV infection who first developed cryoglobulinemic vasculitis after initiation of therapy with the polyethylene glycol (PEG)-conjugated form of IFN (PEG-IFN) and discuss it in the context of the relevant literature. First onset of cryoglobulinemic vasculitis after initiation of IFN therapy has not been described so far.

Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase

Objective To study the efficacy and safety of certolizumab pegol (CZP) in patients with active rheumatoid arthritis (RA) who had discontinued an initially effective TNF inhibitor (TNF-IR). Methods A randomised 12-week double-blind trial with CZP (n=27) or placebo (n=10) followed by an open-label 12 week extension period with CZP. Results Baseline characteristics ofthe 2 groups were similar. ACR20 response (primary end point) at week 12 was achieved in 61.5%, and none of CZP and placebo-treated patients, respectively. Weeks 12–24 showed a maximum effect for CZP at 12 weeks, and that placebo patients switched blindly to CZP attained similar results seen with CZP in weeks 0–12. Since this result was highly significant, study inclusion was terminated after entry of 33.6% of the originally planned 102 patients. Adverse events occurred in 16/27 (59.3%) CZP subjects and 4/10 (40%) placebo subjects. There were no serious adverse events, neoplasms, opportunistic, or serious infections. Conclusions This first, prospective, blinded trial of CZP in secondary TNF-IR shows that the ACR20 response rate observed with CZP was higher than that reported in most previous studies of TNF-IR. Additionally, CZP demonstrated good safety and tolerability. This study supports the use of CZP in RA patients who are secondary non-responders to anti-TNF therapies.

Is radiographic progression of late-onset rheumatoid arthritis different from young-onset rheumatoid arthritis? Results from the Swiss prospective observational cohort

OBJECTIVE RA can be categorized into late-onset RA (LORA, >60-65 years) and young-onset RA (YORA, 30-55 years), depending on the patients age at disease onset. Since the average age of the population is continuously increasing, LORA will most probably gain in importance in the future. Despite this growing importance, LORA has not been the focus of much interest in the past. The aim of this study was to analyse radiographic damage progression of early disease in LORA compared with YORA patients. METHODS We included all patients from the Swiss RA registry, Swiss Clinical Quality Management in RA, with recent-onset arthritis, either RA (disease duration ≤1 year) or undifferentiated arthritis, as diagnosed by the data-entering physician. Patients were followed for 5 years. The cut-off between YORA and LORA was operationally set at 60 years of age. The primary outcome of this study was disease progression and activity, which was assessed based on the 28-joint DAS (DAS28) and the progression of joint erosions using a validated scoring system (Ratingen score). RESULTS A total of 592 patients with early disease were analysed. The age at disease onset had a Gaussian distribution, with a single peak at 54 years of age; 366 patients were categorized as YORA and 226 as LORA at disease onset. DAS28 scores were significantly higher among LORA as compared with YORA patients (4.8 vs 4.5, P = 0.049). Corticosteroids were used in 68% of LORA patients as a first-line treatment, compared with 25.4% in YORA patients (χ(2) test: 54.58; P < 0.0001). In contrast, DMARDs were used in 100% of the YORA patients as first-line treatment, compared with 91.2% of the LORA patients. During follow-up, new glucocorticoids, synthetic DMARDs or biologic DMARDs were initiated in 32.8%, 61.1% and 14.1% of all YORA patients and 17.5%, 54.6% and 6.6% of LORA patients, respectively (χ(2) test: 7.08, 22.53, 54.4; all P < 0.01). The DAS28 scores decreased in both groups during the observed time period, and the initial differences in disease activity vanished after 6 months and during the subsequent follow-up. The Ratingen score was higher in LORA than in YORA patients at inclusion (12.7 vs 5.6, P < 0.0001). The rate of radiographic progression at 5 years was similar when comparing LORA and YORA (3.3 vs 2.6, respectively, P = 0.64). The Ratingen scores at onset and during follow-up over 5 years did not clearly separate LORA and YORA into two groups, but rather, increased linearly when comparing the patients in groups per decade from 20 to 92 years of age. CONCLUSION Our results did not show LORA as a separate subgroup of RA with a different prognosis with regard to radiographic progression.

Differentiation-dependent and stimulus-specific expression of ILA, the human 4-1BB-homologue, in cells of mesenchymal origin

OBJECTIVE Examine the expression of ILA, a member of the human NGF/TNF receptor family and the homologue of the murine 4-1BB, in mesenchymal cells. METHODS ILA mRNA was analyzed by quantitative polymerase chain reaction and Northern blotting in human articular chondrocytes and fibroblasts. ILA protein expression was examined by flow cytometry. RESULTS The proinflammatory stimuli interleukin-1 beta (IL-1 beta), tumour necrosis factor (TNF) alpha, leukemia inhibitory factor (LIF), interferon (IFN) gamma and lipopolysaccharide (LPS) induced ILA mRNA in primary human articular chondrocytes. TGF beta and dexamethasone inhibited IL-1 induced ILA expression. Chondrocytes expressed the 4.8, 4.0 and 1.9 kb isoforms of ILA mRNA which had previously been observed in lymphocytes and additional isoforms at 3.2, 1.5 and 1.2 kb. Cycloheximide alone induced ILA mRNA in primary chondrocytes while the combination of IL-1 and cycloheximide resulted in ILA superinduction. In contrast to primary chondrocytes, activated human synovial or skin fibroblasts did not express ILA mRNA. Furthermore, ILA was no longer inducible by IL-1 in subcultured, dedifferentiated chondrocytes. However, repression of ILA in fibroblasts and dedifferentiated chondrocytes was overcome by cycloheximide and IL-1 further increased ILA mRNA levels in the presence of cycloheximide. Flow cytometric analysis of ILA protein expression with monoclonal antibodies revealed increased cell-surface expression on IL-1 or TNF alpha, but not on TGF beta stimulated chondrocytes. CONCLUSION ILA is not only expressed in the immune system but also in mesenchymal cells. ILA expression is induced by specific stimuli and modulated by the differentiation status of the cells. ILA can serve as a model and marker to analyze differentiation-dependent gene expression in mesenchymal cells.

Use of abatacept in rheumatoid arthritis

Abatacept (CTLA-Ig), a modulator of T-lymphocyte activation, has been approved by the Swiss health regulatory agency Swissmedic for the treatment of active rheumatoid arthritis (RA). This article summarises the key trial findings for this biologic agent in RA in different situations such as early erosive rheumatoid arthritis (RA), biologic-naïve RA, RA before and after the use of methotrexate or TNF-inhibitors and includes safety information from these trials. Based on these data, recommendations for clinical practice in Switzerland are made by a panel of experts.

Effectiveness, tolerability, and safety of subcutaneous methotrexate in early rheumatoid arthritis: A retrospective analysis of real-world data from the St. Gallen cohort.

INTRODUCTION Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment. Recently updated recommendations by the European League Against Rheumatism (EULAR) show MTX as an important part of the first-line strategy in patients with active RA. The study presented here aimed to assess the clinical effectiveness and tolerability of subcutaneous (SC) MTX among patients with RA. METHODS Patients with RA who were naïve at baseline to both conventional and biologic disease-modifying antirheumatic drugs, fulfilled the American College of Rheumatology/EULAR 2010 criteria, and had one or more follow-up visits were selected through sequential chart review for analysis of retrospective data. Patients received SC MTX at varying doses (10-25mg per week). The primary end point was a change in the Disease Activity Score including 28 joints (DAS28); secondary end points included time to employment of the first biologic agent and cumulative MTX doses. RESULTS Overall, 70 patients were in follow-up for a mean of 1.8 years after initiating SC MTX treatment. During this time, 37 (53%) remained on SC MTX without any biologics (MTX-only) and 33 (47%) required the addition of a biologic therapy (MTX-biol). Biologic therapy was required after a mean ± SD of 387 ± 404 days. Mean weekly MTX doses were 17.4mg for patients in the MTX-only group and 19.1mg for patients in the MTX-biol group. Mean baseline DAS28 were similar for patients in the MTX-biol and MTX-only groups (4.9 and 4.7, respectively). Both low disease activity state (LDAS) and remission were achieved by slightly fewer patients in the MTX-biol than MTX-only groups (LDAS, 78.8% vs 81.1%; remission, 69.7% vs 75.7%). Over the full course of the study period, SC MTX was discontinued in 32 patients (46%). Among those who discontinued, the most common reasons were gastrointestinal discomfort (n = 7), lack of efficacy (n = 7), and disease remission (n = 3). Severe infections occurred in 3 patients in the MTX-biol group and 3 patients in the MTX-only group. CONCLUSIONS SC MTX is a safe and effective treatment option for patients with RA. SC MTX resulted in high rates of remission and LDAS in early disease, over prolonged periods of time, it, therefore, may extend the time before patients require initiation of biologic therapy.

Biologic TNF inhibiting agents for treatment of inflammatory rheumatic diseases: dosing patterns and related costs in Switzerland from a payers perspective

BackgroundTo obtain detailed real-life data on costs and dosing patterns in the utilisation of the TNF inhibitors adalimumab, etanercept, and infliximab in patients treated in Switzerland.MethodsAdministrative claims processed by a major Swiss health insurer between 2005 and 2008 were analysed. Patients with inflammatory rheumatic diseases (IRDs) with at least one prescription for adalimumab, etanercept, or infliximab were identified. All-cause and disease-specific costs, as well as daily costs of treatment, were calculated. Dosing patterns and discontinuation rates were analysed.ResultsA total of 555 IRD patients were identified. All-cause costs during the 12 months after the index event were 20,555CHF in the etanercept group, 24,152CHF in the adalimumab group, and 27,614CHF in the infliximab group. The most important cost driver was mean TNF inhibitor drug cost, which was 15,613CHF in the etanercept group, 19,166CHF in the adalimumab group, and 21,313CHF in the infliximab group. Discontinuation rates during the first year after the index event were 46.8% in etanercept, 41.3% in adalimumab, and 51.2% in the infliximab group. Rates of dosage increase were 13.3% in the etanercept group, 13.0% in the adalimumab group, and 14.1% in the infliximab group. When time on treatment was considered, daily costs of treatment were similar for etanercept and adalimumab, but were higher for infliximab.ConclusionsMarked differences in costs between subcutaneous and intravenous therapies were observed. Among the three groups of patients defined by TNF inhibitor treatment, costs for the infliximab group were highest during the year after the index event.

The combination of different antiphospholipid antibody subgroups in the sera of patients with autoimmune diseases is a strong predictor for thrombosis: A retrospektive study from a single center

OBJECTIVE [corrected] To determine the distribution of different antiphospholipid antibodies (APL-Ab) and their association with thrombosis in patients with autoimmune diseases. METHODS Clinical data and laboratory features of 30 patients with different autoimmune diseases with positive APL-Ab were retrospectively studied for a period of more than two years. Anti-cardiolipin (aCL), anti-phosphatidylserine (aPS) and anti-beta2-glycoprotein I (abeta2-GPI) antibodies were determined by ELISA. RESULTS Autoantibodies that target only PS were detected in 53.3% (n = 16) patients, aCL antibodies only were found in one patient (3,3%). In 43.3% (n = 13), aPS were associated with elevated levels of aCL and/or abeta2-GPI antibodies. No thrombotic event occurred in patients with aPS antibodies only compared to 6 patients from the group with different APL-Ab during 808 +/- 92 days of observation. CONCLUSION The combination of different antiphospholipid antibody subgroups seems to be a predictor for thrombosis. The presence of aPS antibodies without additional aCL or abeta2-GPI is not associated with thrombosis. The measurement of the APL specificities in addition to the aCL antibodies may be important to develop predictive markers for the risk to develop thrombotic events.