Pierre Masson

Vaccinations in patients with immune-mediated inflammatory diseases

Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with immunomodulatory or immunosuppressive drugs. In spite of their elevated risk for vaccine-preventable disease, vaccination coverage in IMID patients is surprisingly low. This review summarizes current literature data on vaccine safety and efficacy in IMID patients treated with immunosuppressive or immunomodulatory drugs and formulates best-practice recommendations on vaccination in this population. Especially in the current era of biological therapies, including TNF-blocking agents, special consideration should be given to vaccination strategies in IMID patients. Clinical evidence indicates that immunization of IMID patients does not increase clinical or laboratory parameters of disease activity. Live vaccines are contraindicated in immunocompromized individuals, but non-live vaccines can safely be given. Although the reduced quality of the immune response in patients under immunotherapy may have a negative impact on vaccination efficacy in this population, adequate humoral response to vaccination in IMID patients has been demonstrated for hepatitis B, influenza and pneumococcal vaccination. Vaccination status is best checked and updated before the start of immunomodulatory therapy: live vaccines are not contraindicated at that time and inactivated vaccines elicit an optimal immune response in immunocompetent individuals.

Assessment of damage to the central nervous system by determination of S-100 protein in the cerebrospinal fluid.

S-100 protein was determined by Particle Counting ImmunoAssay in the CSF of patients with various neurological disorders. With a limit of sensitivity of 2.5 micrograms/l this brain-specific protein was detected only in samples from patients with acute damage of the central nervous system, particularly in compression of the spinal cord by tumour, ischaemic disorders, subarachnoïd bleeding and haematoma, and viral or suspected viral infections. Our results support the assumption that S-100 is a reliable index of central nervous system damage and that changes in its concentration could have a prognostic value.

Particle counting immunoassay (Pacia). I. A general method for the determination of antibodies, antigens, and haptens

By using a device designed for counting blood cells, it is possible to measure the agglutination of polystyrene beads (0.8 mu) with accuracy and great sensitivity, the agglutination resulting in a reduction in the number of particles. The latter coated with antigen can be used for determining IgM or IgG antibodies e.g. human rheumatoid factor or rabbit anti-bovine serum albumin antibodies. Macromolecules with multiple antigenic determinants agglutinate particles carrying specific antibodies. This system has been applied for determining HPL and alpha1-fetoprotein with a threshold of sensitivity of about 10 microgram/1. However the agglutination was decreased by serum factors which led to a 10-fold loss of sensitivity. The interference of rheumatoid factor which agglutinated the particles coated with rabbit or goat immunoglobulins could be avoided by reduction of the serum to be analyzed with 5mM dithiothreitol for 5 min. Haptens, i.e. DNP-lysine and T4, were determined by their inhibitory activities toward their specific antibodies, the agglutinator being a hapten-macromolecule conjugate or the antibodies themselves.

The concentration of IgM in the cerebrospinal fluid of neurological patients.

The level of IgM was determined by Particle Counting Immunoassay in the cerebrospinal fluid. In non-neurological patients (N = 20) the mean was 97.5 micrograms/l with the upper reference limit at 380 micrograms/l. The mean IgM index was 0.021 with the upper reference limit at 0.071. Of 21 patients with stroke, 5 had an IgM index exceeding the reference limit. High levels and indices of IgM were observed in most patients (N = 27) with infectious meningo-encephalitis. In this group, the IgM index was abnormal in about 30% of cases with a normal total protein content, and was more often increased than the IgG index. In multiple sclerosis patients (N = 80), the IgM index was increased in 32%. In this disease very high values of IgM index (greater than 0.13) were never associated with very high values of IgG index (greater than 1.8). A significantly higher proportion of males was found in the group of patients with very high values of IgM index (N = 11). No significant influence of the age of onset, the interval between onset and sampling and clinical state was observed. However, of 10 patients with a multiple sclerosis history exceeding 15 years none had an IgM index exceeding the upper reference limit. Four patients with multiple sclerosis had a high IgM index without either an increase of the IgG index or the presence of oligoclonal bands.

Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use

It has long been known that pregnancy and childbirth have a profound effect on the disease activity of rheumatic diseases. For clinicians, the management of patients with RA wishing to become pregnant involves the challenge of keeping disease activity under control and adequately adapting drug therapy during pregnancy and post-partum. This article aims to summarize the current evidence on the evolution of RA disease activity during and after pregnancy and the use of anti-rheumatic drugs around this period. Of recent interest is the potential use of anti-TNF compounds in the preconception period and during pregnancy. Accumulating experience with anti-TNF therapy in other immune-mediated inflammatory diseases, such as Crohn’s disease, provides useful insights for the use of TNF blockade in pregnant women with RA, or RA patients wishing to become pregnant.

The Recognition By Monoclonal-antibodies of Various Portions of a Major Antigenic Site of Human Growth-hormone

The reactivities of five mouse monoclonal antibodies against human growth hormone (hGH) were defined by either a competitive radioimmunoassay with insolubilized antibodies or by an agglutination-inhibition method with hGH-coated polystyrene particles. The five antibodies reacted significantly but to various degrees with human placental lactogen and at least three antibodies reacted with human prolactin and three synthetic peptides extending from residues 19 to 128, 73 to 128 and 98 and 128 of hGH. Four tested monoclonal antibodies failed to react with bovine growth hormone and with hGH oxidized by performic acid. The antibodies were further distinguished by their different reactions with hGH modified by reduction and alkylation or by adsorption on a polystyrene surface. The unique specificity of each antibody was confirmed for most of them by an agglutination method in which the agglutinating activity of hGH was tested on latex particles coated with various paired combinations of the monoclonal antibodies. The lack of agglutination with certain combinations suggested that the specificities of such a pair of antibodies overlapped each other. These results suggest that the sequences corresponding to the synthetic peptides participate in the structure of a major antigenic site of which various portions are recognized by the monoclonal antibodies.

Cancer risk in immune-mediated inflammatory diseases (IMID)

Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86.

The clinical relevance of ferritin concentration in the cerebrospinal fluid.

By means of a new technique (Particle Counting Immunoassay), we have determined the level of ferritin in 470 samples of cerebrospinal fluid of patients with various neurological disorders. The median value obtained in a control group was 2.3 ng/ml with an upper limit at 5.5 ng/ml. the concentrations in the serum and cerebrospinal fluid were independent, but that in cerebrospinal fluid correlated with its total protein content. High values of ferritin were found in infectious meningo-encephalitis, in vascular diseases of the central nervous system, and, unexpectedly, in several cases of dementia without obvious vascular pathology.

Study of IgA in the cerebrospinal fluid of neurological patients with special reference to size, subclass and local production.

IgA was assayed by particle counting immunoassay in cerebrospinal fluid (CSF) from non-neurological and neurological patients. Reference values had a logarithmic normal distribution with a mean of 1.54 mg/l and an upper limit of 5 mg/l. To estimate the possible intra-blood-brain barrier (BBB) production of IgA we have calculated an IgA index: CSF-IgA/serum-IgA: CSF-albumin/serum-albumin. Values higher than the upper reference limit of 0.41 were found in 12 out of 67 patients with multiple sclerosis (18%), in 5 out of 11 with aseptic meningitis, in 7 out of 8 with herpetic encephalitis, in 1 out of 8 with Guillain-Barré syndrome and in 2 cases of tuberculous meningitis. However, this index does not take into account the relative proportions of monomeric and polymeric IgA in CSF and serum. We therefore ultracentrifuged 17 paired CSF and serum samples and determined the relative proportions of monomeric and dimeric IgA and calculated the indices for monomeric and dimeric IgA. In controls the proportion of dimeric IgA in CSF was below 5% of total IgA whereas this proportion was increased up to 53.9% in the case of intra-BBB production of IgA, which is thus characterized by a very high dimeric IgA index. In all cases IgA1 remained the predominant subclass. These results had to be compared with those observed in cultures of peripheral blood lymphocytes, which secrete about equal proportions of monomeric and polymeric IgA pertaining to the IgA1 subclass.

Exacerbation of autoantibody-mediated hemolytic anemia by viral infection.

ABSTRACT Strong enhancement of the pathogenicity of an antierythrocyte monoclonal antibody was observed after infection of mice with lactate dehydrogenase-elevating virus. While injection of the antierythrocyte antibody alone induced only moderate anemia, concomitant infection with this virus, which is harmless in most normal mice, led to a dramatic drop in the hematocrit and to death of infected animals. In vitro and in vivo analyses showed a dramatic increase in the ability of macrophages from infected mice to phagocytose antibody-coated erythrocytes. These results indicate that viruses can trigger the onset of autoimmune disease by enhancing the pathogenicity of autoantibodies. They may explain how unrelated viruses could be implicated in the etiology of autoantibody-mediated autoimmune diseases.