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Kidney disease may substantially alter the absorption, distribution and excretion of the drug methotrexate in patients with rheumatoid arthritis. Researchers monitored concentrations of the medication in 77 arthritis patients. In those with reduced creatinine clearance rates, a measure of kidney insufficiency, methotrexate concentrations were 1.3 to 1.6 times higher than in patients with better kidney function. Drug elimination was also slower in patients with impaired kidney function. Kidney function should guide methotrexate dosing in rheumatoid arthritis patients.

The use of oral contraceptive pills (OCPs) seems to have a protective effect on disease progression, while having several children appears to predict a more severe disease progression in women with rheumatoid arthritis (RA). Researchers evaluated the effects of OCP use, number of children, and breastfeeding on RA disease severity in 176 mothers with RA. More women with mild RA disease had taken OCPs (44%) as compared to those with severe RA disease (21.7%). However, the group of women with severe RA disease was significantly older than those with mild RA disease. There was a 5.75-fold greater risk for severe RA disease in women who had more than three children. Women who breastfed their children had a slightly increased risk for severe RA disease.

Radioactively labeled lymphocytes can aid in diagnosing joint inflammation in patients with rheumatoid arthritis (RA). Lymphocytes are blood cells involved in inflammatory reactions. They congregate in inflamed joints. Measuring their numbers could provide an objective means of measuring the degree of joint inflammation. Eight patients with RA had blood drawn. The lymphocytes were separated and labeled with technetium-99m and reinjected. Scintigraphy was carried out at 30 minutes, 3 hours, and 20 hours after injection on wrists, elbows, shoulders, hips, knees, and ankles. Joint inflammation was also evaluated by scoring pain and swelling, and X rays were taken to evaluate erosion and joint space narrowing. With early stage disease, active arthritis was seen at 30 minutes, intensity increased at 3 hours, and signal persisted at 20 hours. With long standing disease, arthritic joints were seen at 30 minutes, intensity was unchanged at 3 hours, and declined by 20 hours. A stronger signal at 20 hours correlated with higher scores of joint pain and swelling.

Even if NOTCH1is commonly mutated in chronic lymphocytic leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling. CLL patients with a NOTCH1-mutated clone showed low levels of DUSP22 and active chemotaxis to CCL19. Lastly, in xenograft models, NOTCH1-mutated cells displayed a unique homing behavior, localizing preferentially to the spleen and brain. These findings connect NOTCH1, DUSP22, and CCL19-driven chemotaxis within a single functional network, suggesting that modulation of the homing process may provide a relevant contribution to the unfavorable prognosis associated with NOTCH1mutations in CLL.

Human CD38 is a cell surface molecule endowed with multiple functions. As an enzyme, it catalyzes the production of Ca2 active metabolites, predominantly cADPR and ADPR. As a receptor, it regulates the activation of an intracellular signaling pathway, generally linked to lymphocyte activation and proliferation in physiological conditions. The finding that CD38 behaves as an independent negative prognostic factor in CLL patients was the starting point for investigations into the functional role of the molecule in the neoplastic context. Data accumulating in over a decade concur to define a model where CD38 is a central element of a large supramolecular complex that includes surface signaling receptors, chemokine receptors, adhesion molecules and matrix metalloproteases. Expression of CD38 within this supramolecular complex makes signal transduction as well as chemotaxis and homing more efficient, suggesting that the molecule is an integrator of proliferative and migratory signals. These data indicate that CD38 is not only a reliable disease marker but also a functional molecule in the CLL context. The next decade will likely tell whether it can also be a useful therapeutic target.

The February/March 2007 M&B feature titled 'Getting Paid' triggered waves of feedback. Here, the author shares insights from those readers, as well as her additional thoughts. [ABSTRACT FROM AUTHOR]

For caring, nurturing bodyworkers, weaving compassion with proficiency and healthy boundaries can be difficult, but here's an expert's guidance. [ABSTRACT FROM AUTHOR]

People living with dementia respond well to massage. This debut author talks about her experiences working with these individuals. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the expression of a multidrug resistance (MDR) phenotype, implicated in the cellular resistance of tumor to chemotherapy, in rheumatoid synovial membrane. Synovial membrane from 16 rheumatoid (RA) patients was studied. Six patients with osteoarthritis constituted the control group. The cell membrane expression of the glycoprotein Pgp 170, encoded by the MDR 1 gene, was determined by an immunoperoxidase technique using two different monoclonal antibodies (JSB 1, C219). The polymeras chain reaction (PCR) methods were used in parallel to detect the presence of the MDR 1 gene mRNA in the synovial cells. Pgp 170 was expressed on the cell membrane of five RA patients and MDR 1 cellular transcription was detected in one other RA patient. We did not observe any association between synovial glycoprotein expression and age, disease activity, and a specific treatment with a long-acting drug. However, MDR protein expression was associated with the successive treatment with more than three disease-modifying antirheumatic drugs (DMARDs). We conclused that the synovial membrane expresses a glycoprotein recognized by the antibodies JSB 1 and C219. The absence of concomitant MDR 1 transcription suggests the expression of an atypical MDR phenotype in the synovial membrane, distinct from the Pgp 170 encoded by the MDR 1 gene. The implications of the MDR phenotype and the resistance of RA to DMARDs is further discussed.

Sulfasalazine is an efficient treatment for rheumatoid arthritis (RA), but its mode of action is not known. In RA, a correlation has been demonstrated between disease activity and the secretion of immunoglobulin A (IgA) by peripheral blood lymphocytes (PBL) in culture. Furthermore, the IgA-producing cells of the peripheral blood have been shown to originate from the mucous-associate lymphoid tissue (MALT). We studied the variations in the total IgA concentration in the serum of RA patients, and the secretion of IgA by PBL after 7 days culture in vitro, before and after treatment with sulfasalazine. A significant decrease in the serum IgA concentraton was obtained, but there was no modification of the spontaneous increase in the in vitro IgA synthesis by circulating monoclear cells. Our results suggested that the decrease in serum IgA concentration after treatment with sulfasalazine was not linked to a decrease in the IgA secretion by PBL. This does not favour a direct effect of sulfasalazine on the mucous-associated lymphoid tissue.

The pharmacokinetics of total and free methotrexate (MTX) were investigated in 50 patients with rheumatoid arthritis. Each patient received 10 mg MTX intramuscularly. The free and total plasma concentrations of MTX were measured over a 36-h period after drug administration by using the Abbott TDx fluorescence polarization immunoassay. Plasma concentrations of MTX were described by a biexponential function. The mean terminal elimination half-lives of total and free MTX were 9.4 and 8.4 h, respectively, and the corresponding mean residence times, 8.5 and 9.2 h. No difference in these parameters was found by comparing total and free MTX. Total plasma clearance of the free fraction averaged 215 ml/min. The statistical comparison of the variations with time of the ratio of free to total MTX during the 36 h after the dose showed that the free fraction was significantly increased for 8 h after drug administration (p< 0.001). To describe these variations, the changes of the free MTX concentrations (unbound) were related to the changes of the total MTX concentrations by using the Hill equation. Mean plasma protein binding ranged from 20 to 57% for these patients.

Integrin-adressin binding is a critical step in lymphocty attachment to target tissues. The mucosal recognition systems (αEβ7, α4β7, MADcam-1) have been implicated in the autoimmue process in rheumatoid arthritis. We developed a model for in vivo study of radio-labelled lymphocyte circulation and their attachment to human rheumatoid synovium. We studied the homing of tonsil lymphocytes, considered as mucosal lymphocytes, and the involvement of αEβ7 integrin and LFA1 in the homing of tonsil lymphocytes.We engrafted human rheumatoid synovium subcutaneously in 6 week old SCID CB17 mice. Three weeks later, we injected intraperitoneally 20 IO6 human peripheral blood or tonsil mononuclear cells, previously labelled with 3 mCFi HMPAO-99mTc. A mouse total body scintigram was obtained 20 h postinjection. The same protocol was performed after treatment of the MNC and mAb against LFA-1 (CD11a) or αEβ7 (CD103). Tonsil MNC retention in the rheumatoid synovial graft 20 h post-injection was enhanced compared to blood MNC (12731 ± 8297 cpm/200 pixel) versus 5982 ± 4713 cpm/200 pixel, p < 0.05). A monoclonal antibody against LFA 1 decreased the activity in the graft (4152 ± 1287 cpm/200 pixel), p < 0.05. No significant difference in tonsil MNC attachment to rheumatoid synovial tissue was observed with a mAb against αEβ7 (8057 ± 5009 cpm/200 pixel).Our results showed an increase in radiolabelled mucosal MNC migration in synovial tissue engrafted in SCID mice compared with blood MNC. Moreover, the date suggest that LFA-1 but not the αEβ7 integrin is involved in tonsil MNC binding to synovial tissue in RA.

This paper describes a methodology to calculate methotrexate (MTX) pharmacokinetic parameters after intramuscular administration using two samples and the population parameters. Total and free MTX were measured over a 36-h period in 56 rheumatoid arthritis patients; 14 patients were studied after a two-dose scheme at 15-day intervals. The Hill equation was used to relate the free MTX to the total MTX changes in plasma concentrations, and a two-compartment open model was used to fit the total MTX plasma concentrations. A non-linear mixed effect procedure was used to estimate the population parameters and to explore the interindividual variability in relation to the following covariables: age, weight, height, haemoglobin, erythrocyte sedimentation rate, platelet count, creatinine clearance, rheumatoid factor, C-reactive protein, swelling joint count, and Ritchie's articular index. Population parameters were evaluated for 40 patients using a three-step approach. The population average parameters and the interindividual variabilities expressed as coefficients of variation (CV%) were: CL, 6.94 l · h-1(20.5%); V, 34.8 l (32.2%); k12, 0.0838 h-1(47.7%); k21, 0.0769 h-1(61.6%); ka, 4.31 h-1(58%); Emax, 1.12 μmol · l-1(19.7%); γ, 0.932 (12.3%); and EC50, 2.14 μmol · l-1(27.3%). Thirty additional data sets (16 new patients and 14 patients of the previous population but treated on a separate occasion) were used to evaluate the predictive performance of the population parameters. Twelve blood samples were collected from each individual in order to calculate individual parameters using standard fitting procedures. These values were compared to the ones estimated using a Bayesian approach with population parameters as a priori information together with two samples, selected from the individual observations. The results show that the bias was not statistically different from zero and the precision of these parameters was excellent.

The objective of this study was to assess the influence of age on the efficacy and toxicity of methotrexate in rheumatoid arthritis. Four hundred and sixty-nine patients were separated according to the age of onset of methotrexate treatment; before 65 yr (group l, n = 416) and after 65 yr (group 2, n = 53). No difference was found in the evolution of clinical and biological parameters between the two groups. The number of patients in remission at the end of the study was equal. The frequency and type of side-effects were similar. No significant difference was found in the frequency and reasons for methotrexate withdrawal. We noted a trend towards lower therapeutic maintenance of methotrexate when prescribed after the age of 65 yr (P = 0.07, actuarial method). In conclusion, the age at initiation of methotrexate treatment probably did not influence its efficacy and toxicity in rheumatoid arthritis.

We report nine cases of arthritis associated with a monoclonal gammapathy. Joint involvement was noted simultaneously or after the diagnosis of monoclonal gammapathy was made. The cases had oligoarthritis or polyarthritis mimicking rheumatoid arthritis. However, rheumatoid factor was absent in all patients, and distal interphalangeal joints were involved in two cases and sacroiliitis in one. The plasma cell dyscrasia was a multiple myeloma in two cases and monoclonal gammapathy of undetermined significance in the other patients. The light chain isotype was kappa in eight of our patients. A type I cryoglobulinaemia was associated in four cases; it was detected in the synovial fluid of two of them. We suggest that the occurrence of paraproteinaemia with chronic arthritis is more than a chance association. Moreover, a monoclonal gammapathy should be searched for in patients presenting with atypical seronegative arthritis.