Lara Valor

Total serum immunoglobulin levels in patients with RA after multiple B-cell depletion cycles based on rituximab: relationship with B-cell kinetics

OBJECTIVE To investigate whether the incidence of secondary hypogammaglobulinaemia in patients with RA following rituximab was related to patterns of B-cell return and relapse. METHODS CD19(+) B-cell and serum immunoglobulin (sIg) determinations were done every 2 or 3 months in 137 consecutive patients treated with one or more courses of rituximab-based B-cell depletion therapy. The pattern of B-cell return, either concordant or discordant with relapse, was also recorded. RESULTS There were 119 responders. Before treatment, three patients had low IgM and four had low IgG. After the first cycle, low IgM or IgG was present in 9.2% (11/119) and 11.8% (14/119) of the patients, respectively, increasing to 38.8% (8/18) and 22.2% (4/18) after five cycles. The mean percent maximum sIg decrease/cycle was relatively constant. The CD19(+) B-cell count at repopulation was not correlated with immunoglobulin (Ig) levels after each cycle. Patients discordant for B-cell return and relapse developed significantly lower serum IgM and more low IgM episodes than concordant patients (P < 0.05). CONCLUSION Patients with lower baseline sIg levels tended to develop persistent IgM and IgG hypogammaglobulinaemia, resulting from an accumulation of incremental decreases after repeat cycles. This was not due to lower numbers of returning B cells in those developing low sIgs. The association of low IgM in patients with a discordant pattern of relapse suggests that underlying defects in B cells relating to survival and maturation into Ig-secreting cells, as well as attrition of IgG plasma cells may be contributing to low sIg levels in some patients.

Ultrasound joint inflammation in rheumatoid arthritis in clinical remission: how many and which joints should be assessed?

To investigate the sensitivity for detecting subclinical synovitis of different reduced joint ultrasound (US) assessment models as compared with a comprehensive US assessment in rheumatoid arthritis (RA) patients in clinical remission.

Predictive value of Doppler ultrasound-detected synovitis in relation to failed tapering of biologic therapy in patients with rheumatoid arthritis

OBJECTIVE To investigate the predictive value of synovitis detected by Doppler US in relation to failed tapering of biologic therapy (BT) in RA patients in sustained clinical remission. METHODS A total of 77 RA patients (52 women, 25 men) in sustained clinical remission, treated with a stable dosage of BT were prospectively recruited. BT was tapered according to an agreed strategy implemented in clinical practice (i.e. increasing the interval between doses for s.c. BT and reducing the dose for i.v. BT). BT tapering failure was assessed at 6 and 12 months. Doppler US investigation of 42 joints for the presence and grade (0-3) of B-mode synovial hypertrophy and synovial power Doppler signal (i.e. Doppler synovitis) was performed at baseline by a rheumatologist blinded to clinical and laboratory data. Hand and foot radiographs were obtained at baseline and at 12-month follow-up. RESULTS Of the 77 patients, 46 (59.7%) were on s.c. BT and 31 (40.3%) on i.v. BT. At 12 months, 35 patients (45.5%) presented BT tapering failure, 23 of them (29.9% of all patients) in the first 6 months of BT tapering. In logistic regression analysis, the baseline DAS28 and the global score of Doppler synovitis were identified as independent predictors of BT tapering failure at 12 and 6 months. The presence of Doppler synovitis was the strongest predictor for BT tapering failure. No patient showed radiographic progression. CONCLUSION Our results suggest that the presence of Doppler-detected synovitis may predict BT tapering failure in RA patients in sustained clinical remission.

Patient self-assessment and physician’s assessment of rheumatoid arthritis activity: which is more realistic in remission status? A comparison with ultrasonography

OBJECTIVE The objective of this study was to compare disease activity assessed by the patient, the physician and musculoskeletal US in patients with RA in clinical remission. METHODS We evaluated 69 patients with RA in clinical remission according to their attending rheumatologist. Tenderness and swelling in 28 joints were blindly assessed by patients and physicians. The presence of B-mode and Doppler synovitis was blindly investigated in the above joints. The DAS28 and Simplified Disease Activity Index (SDAI) were calculated. RESULTS The percentage of patients in remission according to the self-derived DAS28 (26.1%) was significantly less than that according to the physician-derived DAS28 (52.2%) (P < 0.0005). There was no significant difference in the percentage of patients in remission according to the self-derived SDAI (14.5%) and the physician-derived SDAI (11.6%) (P = 0.172). We found moderate agreement between the patient-derived and physician-derived DAS28 and SDAI [intraclass correlation coefficient (ICC) = 0.620 and ICC = 0.678, respectively]. Agreement between patient and physician was better for the tender joint count (TJC; ICC = 0.509) than for the swollen joint count (SJC; ICC = 0.279). The mean (S.D.) count for B-mode synovitis [4.09 (3.25)] was significantly greater than the SJC assessed by both the patient and physician [2 (3.71) and 1.42 (2.03), respectively] (P < 0.0005 and P = 0.033, respectively). We found moderate agreement between the physician-assessed SJC and the joint count for Doppler synovitis (ICC = 0.528). CONCLUSION Patient-assessed and physician-assessed overall RA activity showed acceptable agreement. Patient self-assessment overestimated disease activity determined by the DAS28. At the patient level, physician-assessed joint swelling showed an acceptable concordance with Doppler US synovitis.

Anti-TNF treatments in rheumatoid arthritis: economic impact of dosage modification

Rheumatoid arthritis (RA) is a chronic systemic disease that leads to increases in health system economic burden through direct and indirect costs, including chronic treatment, reduced productivity and premature mortality. Anti-TNF agents have represented a major advance in the treatment of RA. The most commonly used (adalimumab, etanercept and infliximab) have demonstrated their cost–effectiveness at label doses. However, physicians may need to adapt the treatment by increasing the dose when a drug is not effective enough or by reducing it when there is a sustained effectiveness. In a cross-sectional study conducted in our hospital in which information from RA patients treated with anti-TNF drugs under conventional and modified doses were collected, the authors analyzed the costs of the medication in order to estimate the mean patient-year cost, the annual costs related to clinical efficacy and the cost per responder patient to anti-TNF treatment when dosage modification is undertaken in daily clinical practice.

Comprender el concepto de inmunogenicidad

Immunogenicity is just one of the many benefits of our immune system and is defined as the ability of different substances to trigger an adaptive cellular and humoral cell immune response that is longterm and leads to immunological memory. In rheumatology and other medical specialties such as dermatology, gastroenterology, neurology and immunology, biological proteins derived from biotechnology are increasingly used as therapeutic agents. These proteins, like many other exogenous agents can induce humoral and cellular immune responses. However, in recent years we have noticed how these concepts have been interpreted haphazardly, and sometimes in the wrong way from the point of view of their clinical significance. The immune response or immunogenicity which can be triggered by a therapeutic protein has been proposed as a cause of potential clinical events, including hypersensitivity reactions, decreased effectiveness of the therapeutic molecule and induction of immune processes, including the formation of antibodies against the protein in question.1,2 The most dreaded immunogenicity in clinical terms occurs due to the so-called neutralizing anti-drug antibodies which, as their name implies, have the ability to bind the agent (drug) and neutralize it, preventing its biological or therapeutic function.3 Many factors can influence the immunogenicity of therapeutic proteins, including those inherent to the patient, the disease itself or those related to the product itself. The determinants of patient-related immunogenicity that may predispose unwanted immune responses include the underlying disease, genetic factors and baseline immune status, including associated immunomodulatory therapy. Furthermore, product related factors also influence the probability of inducing an immune response; for example, the route of administration, the type of protein, aspects of the manufacturing process, impurity profile or excipients and formulation characteristics, stability, degradation products or aggregates, dosage, the dosing interval and treatment duration.4–6 The immune response mechanism directed against therapeutic biological molecules seems to be due to “transient” loss of

Prognostic value of peripheral blood mononuclear cell-associated HIV-1 DNA for virological outcome in asymptomatic HIV-1 chronic infection

BACKGROUND Studies in primary HIV-1 infection and advanced HIV-1 disease have demonstrated that HIV-1 DNA associated with peripheral blood mononuclear cells (PBMC HIV-1 DNA) has predictive value for disease progression. OBJECTIVES To analyse in asymptomatic HIV-1 chronic infection the predictive value of PBMC HIV-1 DNA for virological failure. STUDY DESIGN In 115 individuals who had previously participated in study STIR-2102, we retrospectively analysed the PBMC HIV-1 DNA by quantitative real-time PCR. Antiretroviral naïve patients (baseline pre-ART) received 6 weeks of ART prior to randomisation (baseline post-ART). The predictive value of PBMC HIV-1 DNA, HIV-1 RNA in plasma and CD4+ T cells, at baselines pre-ART and post-ART, was determined by Kaplan-Meier and Proportional Hazards Regression analyses. RESULTS At baseline post-ART, 82% of patients showed suppression of HIV-1 RNA, however they maintained significant amounts of HIV-1 DNA (geometric mean: 690 copies/10(6) PBMC). Pre-ART and post-ART levels of HIV-1 DNA and pre-ART levels of HIV-1 RNA showed predictive value (Log-Rank test: p<0.001, p<0.001, p=0.003, respectively). In a multivariate model post-ART PBMC HIV-1 DNA was the stronger predictive variable (adjusted HR, 2.51 [95% CI, 1.33-4.73, p=0.004]) independently of HIV-1 RNA (HR 1.74 [95% CI, 1.16-2.61, p=0.007]). CONCLUSIONS PBMC HIV-1 DNA is an effective prognostic marker for virological outcome in individuals with asymptomatic HIV-1 chronic infection.

Minimum Effective Dosages of Anti-TNF in Rheumatoid Arthritis: A Cross-sectional Study

AIMS To evaluate the modified dosages of anti-TNF in controlling disease activity in rheumatoid arthritis (RA) measured by DAS28-ESR. PATIENTS AND METHODS Cross-sectional study: RA patients treated with etanercept (ETN), adalimumab (ADA) or infliximab (IFX), at standard or modified doses. MAIN VARIABLES dosage, concomitant disease modifying drugs (DMARDs), DAS28-ESR. RESULTS 195 RA patients included (79% women, mean age 58.1 years): ETN=81, ADA=56, IFX=58. Mean disease duration and time to first biological treatment was higher in IFX group (P=.01). Patients distribution by dosage: standard: ETN (72.8%), ADA (69.6%), IFX (27.6%); escalated: IFX (69%), ADA (5.4%), ETN (0%); reduced: ETN (27.1%), ADA (25%), IFX (3.4%). Concomitant DMARDs use was lower in ETN (58.2%) than ADA (66.07%) and IFX (79.31%). Higher proportion of responders (DAS28 ≤3.2) in ADA (65.3%) and ETN (61.7%) than IFX (48.3%). CONCLUSIONS RA clinical control can be preserved with modified anti-TNF dosages. Controlled prospective studies should be performed to define when therapy can be tailored and for which patients.

Los inhibidores de las proteínas-cinasas en enfermedades autoinmunes e inflamatorias: presente y futuro de nuevas dianas terapéuticas

Although advances in biological medicine have seen significant progress in the treatment of autoimmune and inflammatory disease, many patients do not experience a satisfactory response. Hence, there are two challenges facing the medical research community. The first is to continue development in the field of existing biological therapies, such as monoclonal antibodies. The second is to open new frontiers of research and explore treatment alternatives for non-responders to other therapies. Attention has increasingly turned to the therapeutic potential of small molecule weight kinase inhibitors (SMKIs), currently used extensively in oncology and haematology. Initial research into the therapeutic value of SMKIs for autoimmune and inflammatory diseases has been encouraging. SMKIs are taken orally, which reduces cost for the health provider, and could increase compliance for the patient. This is why research is now focusing increasingly on SMKIs as a new generation line of treatment in these diseases. Tofacitinib, an inhibitor of Janus-kinase, is currently the only drug approved for the treatment of rheumatoid arthritis by FDA. However, much more needs to be done to understand the intracellular signalling pathways and how these might affect disease progression before solid conclusions can be drawn.

Estudio comparativo de las 2 versiones de un inmunoanálisis comercializado para la monitorización terapéutica de adalimumab en artritis reumatoide

OBJECTIVE To describe the results of the comparative study between both versions of an immunoassay commercialized for therapeutic drug monitoring of adalimumab (ADA) in rheumatoid arthritis (AR). MATERIAL AND METHODS 140 samples of patients with RA treated with ADA 40mg every 14 days were analyzed by both versions of the test (V1 or previous and V2 or updated). RESULTS A good correlation was obtained by both versions. In general V2 provides higher results of ADAs concentration than V1 and presents greater precision in the range of concentrations for clinical decisions, adjusting for the real concentration of the drug in blood. In addition, V2 allows for complete automation, which simplifies the analysis and reduces significantly the variability. CONCLUSION ADAs monitoring with the updated version demonstrated to have technical significant advantages, constituting a more practical tool for therapeutic decisions in patients with RA.