Oral anti‐CD3 immunotherapy for HCV‐nonresponders is safe,promotes regulatory T cells and decreases viral load and liver enzyme levels: results of a phase‐2a placebo‐controlled trial

Orally administered anti‐CD3 antibodies are biologically active in the gut through induction of regulatory T cells, exert an immune‐modulatory effect, and alleviate insulin resistance and liver damage in patients with NASH. Aims: To determine the safety of oral anti‐CD3 monoclonal antibody (MAb) immunotherapy in chronic HCV patients with associated immune dysfunction. Methods: Four groups (n = 9) of chronic HCV patients who were nonresponders to interferon plus ribavirin therapy received oral placebo (group A) or anti‐CD3 MAb at one of three dosage levels for 30 days. Patients were followed for safety parameters and serum levels of liver enzymes, virus, cytokines and regulatory T cells. Results: Oral anti‐CD3 immunotherapy was safe and well tolerated; no treatment‐related adverse events were noted. The following improvements were noted relative to pretreatment levels: HCV viral load and AST and ALT levels decreased in the low‐ and high‐dose groups following 30 days of therapy. In two of the treated groups, an increase in regulatory T cells (CD4⁺ CD25⁺) was noted. The positive effects were somewhat more apparent in subjects with initially elevated liver enzyme levels. Conclusions: Oral anti‐CD3 MAb immunotherapy for nonresponder HCV patients was safe and well tolerated. Trends and statistically significant improvements were observed as reductions in viral load and liver enzyme levels, along with an increase in regulatory T‐cell levels. These data support a role for the immune system in the pathogenesis of HCV infection and suggest that this immunotherapy is worthy of evaluation in combination with HCV antiviral drugs.     

Chemoprevention of colorectal cancer with nonsteroidal anti‐inflammatory drugs

Colorectal carcinoma is one of the commonest solid organ tumors in the world and its prevalence appears to be increasing in Asia. Recently, there has been much interest in various chemotherapeutic agents for the management of this condition, in particular nonsteroidal anti‐inflammatory drugs (NSAIDs). There is a large amount of data that suggest traditional NSAIDs, as well as the new cyclooxygenase (COX)‐2 selective inhibitors such as rofecoxib and celecoxib, have a role in the setting of primary and secondary prevention, and adjuvant therapy of both sporadic colorectal carcinoma and familial adenomatous polyposis. This review examines some of this data, as well as the potential problems and limitations of using these agents, particularly in light of the recent withdrawal of rofecoxib.     

Choosing and using non‐steroidal anti‐inflammatory drugs in haemophilia

The management of pain and inflammation in haemophilic arthropathy is challenging due to the lack of anti‐inflammatory analgesic agents perfectly suitable for this population. Non‐steroidal anti‐inflammatory drugs (NSAIDs) are widely used in the management of arthritis due to their analgesic and anti‐inflammatory effects. Their use in persons with haemophilia (PWH), however, is limited due to increased risk of bleeding mainly from the upper gastrointestinal (UGI) tract. Cyclooxygenase‐2 (COX‐2) selective NSAIDs which have comparable analgesic effect to traditional NSAIDs (tNSAIDs) but with less UGI bleeding have been considered to be a suitable option for treatment of haemophilic arthropathy. COX‐2 inhibitors, however, have an increased in the risk of cardiovascular (CV) disease. Although the atherosclerotic burden in PWH is similar to that in the general population, the risk of CV‐related deaths is lower. PWH have a higher risk of GI bleeding and lower risk of thrombotic disease compared to general population. Therefore, when PWH require anti‐inflammatory/analgesic agents, it seems reasonable to use lowest dose of COX‐2 inhibitors for the shortest period together with a proton pump inhibitor. Helicobacter pylori infection should be tested for and eradicated prior to starting NSAID treatment in PWH. Furthermore, regular blood pressure and renal function test monitoring is required during COX‐2 inhibitor treatment.     

Kinetics of the interaction between anti‐FVIII antibodies and FVIII from therapeutic concentrates,with and without von Willebrand factor,assessed by surface plasmon resonance

The presence of VWF in plasma‐derived FVIII (pdFVIII/VWF) products has been pointed out as a key difference with recombinant FVIII (rFVIII) products with regard to immunogenicity. A Surface Plasmon Resonance (SPR) study was designed to characterize in detail the interaction between anti‐FVIII (IgGs) from a severe haemophilia A patient, and FVIII from concentrates of different sources. Full‐length rFVIII (preincubated or not with purified VWF), B domain‐deleted (BDD)‐rFVIII and pdFVIII/VWF were analysed. To ensure reproducible conditions for accurate determination of kinetic constants, a capture‐based assay format was developed using protein G surfaces for specific and reversible coupling of endogenous anti‐FVIII antibodies. Concentration ranges (nm ) of FVIII products tested were 9–0.03 (rFVIII) and 6–0.024 (pdFVIII/VWF). The association with antibodies was monitored for 3–5 min, whereas dissociation of the complex was followed for 5–20–240 min. A strong interaction of rFVIII and BDD‐rFVIII with patient's IgG was detected with the K _D values in the low picomolar range (5.9 ± 3.0 and 12.7 ± 6.9 pm , respectively) and very slow dissociation rates, while pdFVIII/VWF showed only marginal binding signals. The VWF complexed rFVIII displayed reduced binding signals compared with uncomplexed rFVIII, but the K _D was still in the picomolar range (4.1 ± 1.9 pm ) indicating insufficient complex formation. rFVIII, alone or bound to exogenously added VWF, showed high affinity for anti‐FVIII IgGs from a severe haemophilia A patient whereas pdFVIII/VWF did not. These results are in agreement with those studies that point towards rFVIII concentrates to be more immunogenic than pdFVIII concentrates.     

Glucose‐dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin‐1‐dependent manner in mice

Recently, glucagon‐like peptide‐1 (GLP‐1) levels have been found to be increased in response to inflammatory stimuli, leading to insulin secretion and prevention of hyperglycaemia during endotoxemia in mice. In the present study, we assess the relevance of the other incretin hormone, glucose‐dependent insulinotropic peptide (GIP), as a regulator of glucose metabolism under inflammatory conditions. We found that lipopolysaccharide (LPS) increased GIP secretion in a time‐ and dose‐dependent manner in C57BL/6J mice. To elucidate the underlying mechanisms, mice were injected with inflammatory cytokines known to be released by LPS. Circulating GIP levels significantly increased in response to interleukin (IL)‐1β but not IL‐6 or tumour necrosis factor (TNF)‐α administration. Using respective knockout mice we found that LPS‐mediated GIP secretion was selectively dependent on IL‐1 signalling. To evaluate the functional relevance of inflammatory GIP secretion we pretreated mice with the GIP‐receptor antagonist (Pro3)GIP. This blunted LPS‐induced TNF‐α and IL‐6 secretion but did not affect LPS‐induced insulin secretion or blood glucose‐lowering. In conclusion, GIP provides a novel link between the immune system and the gut, with proinflammatory‐immune modulatory function but minor glucose regulatory relevance in the context of acute endotoxemia.     

Severe cryptococcal‐associated neurological immune reconstitution inflammatory syndrome in a renal transplant recipient treated with adalimumab

Cryptococcosis is a major concern in organ transplant recipients. A decrease in immunosuppressants following the initiation of antifungal therapy is currently recommended, but can occasionally be complicated by the onset of immune reconstitution inflammatory syndrome (IRIS). We report on a case of cryptococcosis in a kidney transplant recipient, compounded by severe neurological IRIS, the outcome of which was unfavorable despite the use of anti‐tumor necrosis factor‐alpha monoclonal antibodies.     

A recombinant cystatin from Ascaris lumbricoides attenuates inflammation of DSS‐induced colitis

Helminthiasis may ameliorate inflammatory diseases, such as inflammatory bowel disease and asthma. Information about immunomodulators from Ascaris lumbricoides is scarce, but could be important considering the co‐evolutionary relationships between helminths and humans. We evaluated the immunomodulatory effects of a recombinant cystatin from A. lumbricoides on an acute model of dextran sodium sulphate (DSS)‐induced colitis in mice. From an A. lumbricoides cDNA library, we obtained a recombinant cystatin (rAl‐CPI). Protease activity inhibition was demonstrated on cathepsin B and papain. Immunomodulatory effects were evaluated at two intraperitoneal doses (0.5 and 0.25 μg/G) on mice with DSS‐induced colitis. Body weight, colon length, Disease Activity Index (DAI), histological inflammation score, myeloperoxidase (MPO) activity, gene expression of cytokines and cytokines levels in colon tissue were analysed. Treatment with rAl‐CPI significantly reduced DAI, MPO activity and inflammation score without toxic effects. Also, IL‐10 and TGF‐B gene overexpression was observed in rAl‐CPI‐treated group compared to DSS‐exposed control and healthy mice. Furthermore, a reduction in IL‐6 and TNF‐A expression was found, and this was confirmed by the levels of these cytokines in colonic tissue. In conclusion, rAl‐CPI reduces inflammation in a mouse model of DSS‐induced colitis, probably by increasing the expression of anti‐inflammatory cytokines and reducing pro‐inflammatory ones.     

The infectious profiles of anti‐tumor necrosis factor agents in a Thai population: a retrospective study a the university‐based hospital

Aims: Anti‐tumour necrosis factor‐α (anti‐TNF) agents represented treatment advances in a number of rheumatologic diseases. However, adverse effects of anti‐TNF agents have been identified through both clinical trials and post‐marketing surveillance, especially an increased risk of serious infections. This study firstly described the infectious profiles of anti‐TNF agents in a Thai population. Methods: We retrospectively reviewed all infectious incidences from 100 consecutive medical records of patients who were treated with either etanercept or infliximab for any rheumatologic and non‐rheumatologic conditions. Results: Indications for anti TNF‐α agents were mainly rheumatoid arthritis (46%) and spondyloarthropathy (SpA) (41%). Seventy‐seven patients were treated with etanercept and 23 with infliximab. For those whose initial treatment was etanercept, there were two events of suspected active pulmonary tuberculosis (TB) and suspected hepatitis‐B virus (HBV) reactivation. Two out of 23 patients (8.7%) who were firstly treated with infliximab had herpes zoster skin infection. Incidence of overall infection before anti‐TNF treatment were significantly higher in patient who started with etanercept (0.065 vs. 0.019 cases per person‐years in etanercept and infliximab respectively, P < 0.0001). Incidence of overall infection post‐anti‐TNF treatment were 0.122 and 0.201 cases per person‐years in patients who started with etanercept and infliximab with no significant difference (P > 0.05). The overall infection rates were significantly increased after infliximab treatment (P < 0.0001). Conclusion: Even thought there were two new events of TB and HBV reactivation after etanercept treatment, incidence of overall infection seemed to be increased after infliximab treatment. The infectious screening and monitoring with high index of suspicion as well as the pre‐emptive treatment are still important whenever either etanercept or infliximab is started.     

Paradoxical psoriasiform reactions of anti‐tumour necrosis factor therapy in inflammatory bowel disease patients

Anti‐tumour necrosis factor (TNF) agents have demonstrated efficacy in inflammatory bowel disease (IBD). Cutaneous reactions such as new onset psoriasis or psoriasiform‐like reactions are among the most common adverse reactions. We retrospectively identified cases of anti‐TNF‐induced psoriasis or psoriasiform manifestations in IBD patients at a tertiary centre in Australia. A total of 10 (six females) of 270 (3.7%) IBD patients treated with anti‐TNF therapy developed drug‐induced psoriatic or psoriasiform‐like reactions: five patients were treated with infliximab and five with adalimumab; nine had Crohn disease. The time from initiation of anti‐TNF agent to onset of rash was 7.5 months on average. The most frequent distributions were the scalp (7/10) and extremities (6/10). Three patients discontinued anti‐TNF treatment with resolution of the rash. Topical treatment of the lesions allowed continued use of biological agent in the majority. Paradoxical psoriatic lesions are recognised adverse events associated with anti‐TNF therapy, but discontinuation of therapy due to dermatological complications is required only rarely, even in patients with psoriasiform lesions.