OBJECTIVE:To study the levels of rituximab (RTX) and anti-RTX antibodies (ARAs) in patients with rheumatoid arthritis (RA) at 30, 90, and 180 days after the first infusion, in relation to clinical and serological parameters and B cell homeostasis.METHODS:Thirty-four patients with RA who failed to respond to anti-tumor necrosis factor therapy received RTX. At baseline, 4, 12, and 24 weeks after the first infusion of RTX, we performed a clinical assessment and determined the levels of RTX, ARAs, B cells, rheumatoid factors, anti-cyclic citrullinated peptide antibodies, immunoglobulins, and complements.RESULTS:RTX levels varied widely among patients. No ARAs were detected during the follow-up. Patients with lower levels of RTX presented with higher decreases in erythrocyte sedimentation rate, immunoglobulins, and complement 6 months after the first infusion. Patients with higher levels of RTX showed a higher B cell depletion at 90 days but an earlier B cell recovery than those with lower levels of RTX. No differences in clinical response were observed between the two groups at 6 months after starting the treatment.CONCLUSION:Our findings suggest that RTX levels in the serum of patients with RA are related to B cell homeostasis and the severity of immunological parameters but not to the clinical response at 6 months.

Adalimumab is a fully human anti–tumor necrosis factor α (anti-TNFα) monoclonal antibody that specifically blocks the interaction of TNFα with its receptors. It binds both soluble and transmembrane TNFα. We hypothesized that blocking these TNFα signals regulates the altered TNFα production in rheumatoid arthritis (RA) patients.

Rituximab therapy alters all aspects of B‐cell participation in the disturbed immune response of rheumatoid arthritis patients. To determine the impact of B‐cell depletion on other immune compartments, we analysed levels of soluble and surface interleukin‐15 (IL‐15) along with the frequency of IL‐15‐related subsets after rituximab treatment. We then studied the correlation of observed changes with clinical activity. Heparinized blood samples from 33 rheumatoid arthritis patients were collected on days 0, 30, 90 and 180 after each of three rituximab cycles. Serum cytokine levels were determined by ELISA. Interleukin‐15 trans‐presentation was analysed by cytometry. Flow cytometry with monoclonal antibodies was performed to analyse circulating cell subsets. Interleukin‐15 was detected in the serum of 25 patients before initiating the treatment. Rituximab then progressively reduced serum IL‐15 (138 ± 21 pg/ml at baseline, 48 ± 18 pg/ml after third cycle, P = 0·03) along with IL‐17 (1197 ± 203 pg/ml at baseline, 623 ± 213 pg/ml after third cycle, P = 0·03) and tended to increase the frequency of circulating regulatory T cells (3·1 ± 1 cells/μl at baseline, 7·7 ± 2 cells/μl after third cycle). Rituximab also significantly decreased IL‐15 trans‐presentation on surface monocytes of patients negative for IL‐15 serum (mean fluorescence intensity: 4·82 ± 1·30 at baseline, 1·42 ± 0·69 after third cycle P = 0·05). Reduction of serum IL‐15 was associated with decrease in CD8+ CD45RO+/RA+ ratio (1·17 ± 0·21 at baseline, 0·36 ± 0·06 at third cycle, P = 0·02). DAS28, erythrocyte sedimentation rate and C‐reactive protein correlated significantly with CD8+ CD45RO+/RA+ ratio (R = 0·323, R = 0·357, R = 0·369 respectively, P < 0·001). Our results suggest that sustained clinical improvement after rituximab treatment is associated with IL‐15/memory T‐cell‐related mechanisms beyond circulating B cells.

ABSTRACTExpression of the scavenger receptor CD36 on lymphocytes is intriguing. We observed that a minor subpopulation of lymphocytes expressed CD36 on the cell surface. We investigated the source of CD36 and also the proliferation and cytokine production of these CD36+ CD4+ lymphocytes. Flow cytometry analysis and immunofluorescence microscopy showed that CD36+ platelets were responsible for CD36 detection on lymphocytes. CD36 was then used as a tool to characterize lymphocytes with bound platelets. Activation-induced proliferation was lower in CD4+ lymphocytes with bound platelets than lymphocytes without bound platelets. IL-17 and IFN-γ production was also reduced in lymphocytes with bound platelets. We then studied the presence of CD36+ CD4+ lymphocytes in RA patients. We observed that the percentage of CD4+ lymphocytes with bound platelets was higher on RA patients than in healthy donors. RA patients with higher titers of anti-CCP, RF levels, and cardiovascular risk index presented a lower percentage of CD4+ lymphocytes with bound platelets. These patients also had higher IL-17 and IFN-γ production. These results suggest that platelet-binding modifies lymphocyte function. This binding could be a regulatory mechanism in RA that confers a less severe phenotype.

En la actualidad existen en España tresfármacos con la indicación de reducción de la uricemia. Esos tresfármacos (alopurinol, febuxostat y benzbromarona) tienen una eficacia de alrededor del 90%. En cambio, distintos estudios muestran que los enfermos con gota, en general, no están bien tratados, y no se consiguen uricemias por debajo de los 6mg/dl. En este trabajo se discuten los distintos tratamientos farmacológicos y no farmacológicos reductores de la uricemia, se intenta entender el porqué de la baja efectividad de estas terapias y se explican diversas intervenciones que pueden ayudarnos a mejorarla.

OBJECTIVE:To compare the effectiveness and safety of a combination of rituximab (RTX) with either methotrexate (MTX) or leflunomide (LEF) in the treatment of patients with active rheumatoid arthritis (RA) and inadequate response to anti-tumor necrosis factor agents or traditional disease-modifying antirheumatic drugs (DMARD) in a real-world setting. METHODS:Data from 77 consecutive unselected patients with active RA and treated with at least 1 cycle of RTX (1 g × 2 weeks) plus MTX or LEF were retrospectively collected. A comparative study between the 2 combinations of treatment (RTX+MTX and RTX+LEF) was performed at 6 months of follow-up considering 3 outcomes: the improvement of RA disease activity, the evolution of functional disability, and the tolerability and side effect profile. RESULTS:Of the 77 patients, 45 received RTX+MTX and 32 RTX+LEF. At baseline there were no significant differences between the groups in terms of the main clinical and laboratory data, or in the number of previous DMARD and anti-tumor necrosis factor agents used. At 6 months of follow-up, we did not find significant differences between the 2 combinations in the evolution of RA disease activity (DAS28 response, according to the European League Against Rheumatism (EULAR) improvement criteria) and functional disability progression (health assessment questionnaire) over time. Minor adverse events occurred in 9% of RTX+MTX patients and in 9% of RTX+LEF patients. None of the patients had serious adverse events and none discontinued the treatment during the study period. CONCLUSIONS:Our preliminary data support the view that LEF is a useful alternative if MTX is contraindicated, since its effectiveness and safety seem similar.

Despite major advances in understanding the pathogenesis of autoimmune diseases, the etiopathogenic factors responsible for the breakdown of self-tolerance mechanisms and the potential triggering mechanisms remain unknown. It is generally accepted that genetic predisposition and environmental factors may play a key role in the development of these polygenic and multifactorial diseases. Infectious agents are among the environmental elements presumably involved in their development. In some illnesses, such as reactive arthritis, rheumatic fever, or vasculitis associated with hepatitis B or C virus, the inciting microbial agent is relatively well defined. Because vaccines contain inactive viral or bacterial products, or attenuated living microorganisms, they may operate as autoimmune disease-triggering agents. Although several cases of autoimmune diseases appearing immediately after vaccination have been reported, attempts to establish a clear, causal relationship as yet have been unsuccessful. We describe 2 further cases: giant cell arteritis(GCA) that appeared after an influenza vaccine, and rheumatoid arthritis(RA) that was detected after immunization with an influenza vaccine and tetanus toxoid.

Rituximab therapy for refractory systemic-onset juvenile idiopathic arthritisSystemic-onset juvenile idiopathic arthritis (SOJIA), formerly called Still's disease, is a subset of juvenile arthritis that describes patients with fever, rash, arthritis, serositis and visceromegaly.][3][4][5][6] However, this therapeutic arsenal is unable to control the disease in all patients.Recently, rituximab, a chimeric anti-CD20 monoclonal antibody, has been successfully used in two patients with refractory adult-onset Still's disease. 7As the similarity of clinical and laboratory features present in SOJIA and adultonset Still's disease implies that these conditions have similar pathogenic mechanisms, 1 2 we tested rituximab in three patients with severe active SOJIA who had an inadequate response or were intolerant to current treatment options.The patients' main characteristics at rituximab treatment initiation and outcome data are summarised in table 1.In all cases the disease persisted into adulthood, and at the time of the study