Rituximab Therapy In Rheumatoid Arthritis Research Articles

Delayed Diagnosis of West Nile Meningoencephalitis in a Patient Receiving Rituximab for Rheumatoid Arthritis

West Nile virus (WNV) neuroinvasive disease is associated with substantial morbidity and mortality. Clinical suspicion is usually confirmed with cerebrospinal (CSF) immunoglobulin M (IgM) detection using enzyme-linked immunoassay (ELISA) techniques. CSF polymerase chain reaction (PCR) is rarely used to confirm the disease and is not widely available. We present a detailed report offalse-negative WNV IgM in a patient receiving rituximab therapy for rheumatoid arthritis. She was exposed to the virus during peak immunosuppression and strong clinical suspicion was confirmed with WNV PCR, illustrating the importance of such consideration with the recent incremental use of rituximab therapy.Despite the lack of specific anti-viral treatment for WNV, delayed consideration and diagnosis of WNV in those who are immunosuppressed would expose them to a wide panel of testing, with a subsequent increase in the cost of medical care.

Expert Panel consensus statements on the optimal usage of rituximab for the management of rheumatoid arthritis in India

Pharmacological management of rheumatoid arthritis (RA) includes synthetic and biological disease-modifying antirheumatic drugs (DMARDs). Biological DMARDs, also referred to as “biologics,” rapidly retard progression of the joint damage seen in RA. Rituximab is a well-established biologic for the management of RA with several biosimilar versions available. This document presents the consensus statements on the usage of rituximab for the management of RA developed by a group of 14 experienced rheumatologists from India. This expert panel identified areas of interests, collated and summarized relevant literature, developed, debated and refined and revised the statements which were voted upon at relevant stages. Subsequently, a wider consultative process including voting on the draft statements involved 18 more rheumatologists from across India. The approved final version has 28 consensus statements related to the following seven areas of rituximab therapy in RA, namely, contraindication, pretreatment screening, treatment schedule, evaluation of response, safety, and research agenda for future. It is envisaged that these consensus statements would help in optimizing the usage of rituximab in RA not only in India but also in other countries and benefit all stakeholders.

Non-response to rituximab therapy in rheumatoid arthritis is associated with incomplete disruption of the B cell receptor repertoire

ObjectiveTo gain more insight into the dynamics of lymphocyte depletion and develop new predictors of clinical response to rituximab in rheumatoid arthritis (RA).MethodsRNA-based next-generation sequencing was used to analyse the...

A comprehensive review of rituximab therapy in rheumatoid arthritis patients.

Rituximab (RTX) is an approved treatment for rheumatoid arthritis (RA) patients that do not respond adequately to disease-modifying antirheumatic drugs. However, different new concerns, such as efficacy, optimum dose, safety issues, prediction of response to RTX, and pregnancy outcomes have attracted a lot of attention. The PubMed database was systematically reviewed for the last published articles, new findings, and controversial issues regarding RTX therapy in RA using "Rheumatoid arthritis" AND "rituximab" keywords, last updated on June 18, 2019. From 1812 initial recorders, 162 studies met the criteria. Regarding the optimum dose, low-dose RTX therapy (2 × 500mg) seems as effective as standard dose (2 × 1000 mg), safer, and more cost-effective. The most common reported safety challenges included de novo infections, false negative serologic tests of viral infections, reactivation of chronic infections, interfering with vaccination outcome, and development of de novo psoriasis. Other less reported side effects are infusion reactions, nervous system disorders, and gastrointestinal disorders. Lower exposure to other biologics, presence of some serological markers (e.g., anti-RF, anti-CCP, IL-33, ESR), specific variations in FCGR3A, FCGR2A, TGFβ1, IL6, IRF5, BAFF genes, and also EBV-positivity could be used to predict response to RTX. Although there is no evidence of the teratogenic effect of RTX, it is recommended that women do not expose themselves to RTX at least 6months before the conception. Only a reversible reduction of B cell-count in the offspring may be the pregnancy-related outcome. Although RTX is an effective therapeutic option for RA, more studies on optimum doses, prevention of RTX-related side effects, prediction of RTX response, and safety during the pregnancy are required.

THE ROLE OF LABORATORY BIOMARKERS IN PREDICTING THE EFFICIENCY OF RITUXIMAB THERAPY FOR RHEUMATOID ARTHRITIS: NEW EVIDENCE

Rheumatoid arthritis (RA) is the most common and severe chronic joint inflammatory disease leading to early disability and shorter lifespan in patients. A number of studies have demonstrated that short-term and long-term prognosis of the disease is much more favorable in achieving remission in the early stages of the disease; however, the efficacy of drugs varies widely from patient to patient, which is due to the heterogeneity of the disease itself and to a number of other causes. In this connection, the problem of searching for biomarkers that allow the personalized choice of a treatment regimen in each specific case remains relevant as before. Rituximab (RTM) that is a chimeric monoclonal antibodies against CD20 membrane antigen of B cells causing the depletion of various B lymphocyte subpopulations is one of the effective and safe drugs used to treat RA. Compared to other biological agents, RTM has a long-term efficacy of one treatment cycle, which persists for 6 months or more. The current literature presents a large amount of data on the role of cellular and molecular biomarkers in predicting the efficiency of RTM therapy for RA, some of which are considered in this review.

Effects of Rituximab and Dexamethasone on Regulatory and Pro-Inflammatory B-Cell Subsets in Patients with Primary Immune Thrombocytopenia

BackgroundB-cell depletion with rituximab (RTX) is widely accepted as first- or second-line therapy in primary immune thrombocytopenia (ITP), but it is still unclear how RTX mediates its positive effect in ITP patients. RTX has been reported to induce a reduced titer of platelet antibodies. However, this finding is inconsistent and other B-cell functions, such as the ability to secrete cytokines or to function as antigen-presenting cells for T cells, may be involved in the pathogenesis of ITP. Evidence suggests that B cells participate in the regulation of autoimmune diseases by virtue of their ability to produce the regulatory cytokines interleukin (IL)-10, IL-35, or transforming growth factor β. The various functions of B cells involved in the pathogenesis of autoimmune diseases can in part be deducted by their phenotype as recognized by measurement of specific surface markers and cytokine secretion.Materials and MethodsWe previously conducted a trial involving 137 newly diagnosed adult ITP patients randomized to treatment with RTX (375 mg/m2/week for 4 weeks) + dexamethasone (DXM) (40 mg/day for 4 days repeated up to 6 cycles) or DXM monotherapy. From this cohort, we identified 16 patients with available samples of peripheral blood mononuclear cells (PBMCs) at baseline and 12 months after treatment; 9 patients from the RTX+DXM group, 7 patients from the DXM group. Seven anonymous blood donors served as healthy controls.PBMCs were incubated for 18 h at 37°C under 5% CO2 in RPMI-1640 containing 10% (v/v) serum from healthy blood group AB donors, either alone or stimulated with 10 µg/ml CpG oligodeoxynucleotides. Expression of the cell-surface markers CD5, CD27, CD25 and CD19, and intracellular content of IL-6 and IL-10 were measured by flow cytometry.ResultsAll patients responded to therapy and were in complete or partial remission at 12 months. Patient characteristics are listed in table I.We observed a significant increase in the proportion of CD5+ B cells 12 months after treatment with RTX+DXM compared to baseline (p < 0.01, Fig. 1A). The percentage of CD27+ memory B cells was significantly decreased at 12 months compared to baseline in patients receiving RTX+DXM (p < 0.05, Fig. 1B), and there was an inverse correlation between platelet numbers and the proportion of CD27+ B cells (R = -0.71; p < 0.05). The proportion of CD25+ B cells tended to decrease in patients treated with RTX+DXM, and was lower at 12 months than in patients treated with DMX only (p < 0.05, Fig 1C).PBMCs from ITP patients contained a lower proportion of IL-10+ B cells (p < 0.01) as well as a lower proportion of B cells producing IL-6 (p < 0.01) at baseline than PBMCs from healthy controls. At 12 months the low proportions had normalized in both treatment groups (Fig. 2).ConclusionB cells from ITP patients treated with RTX+DXM contained a high proportion of CD5+ B cells and low proportions of CD25+ and CD27+ B cells. Before treatment, B cells from ITP patients contained low frequencies of IL-10+ and IL-6+ B cells. Treatment with RTX + DXM or DXM alone reverted these aberrancies to normal. The increase in IL-10+ B cells as well as CD5+ B cells, which may represent overlapping subsets, is compatible with induction of Bregs and may support Treg development. Given the role of CD5+ B cells in maintenance of tolerance, the high frequency of these cells, which has also been observed after RTX therapy in rheumatoid arthritis, is compatible with amelioration of disease. [Display omitted] [Display omitted] [Display omitted] DisclosuresGudbrandsdottir:GSK: Research Funding; Amgen: Research Funding.

Epstein-Barr virus in peripheral blood is associated with response to rituximab therapy in rheumatoid arthritis patients.

Autoreactive B cells infected by Epstein-Barr virus (EBV) are suspected to be involved in the etiology of various human chronic autoimmune diseases. This motivated us to study the relationship between peripheral blood EBV load at baseline and treatment response to B cell-depleting therapy in rheumatoid arthritis (RA) patients. Thirty-five RA patients who started treatment with rituximab (RTX) in a routine clinical setting were assessed for baseline disease activity using disease activity score using 28 joint counts (DAS28) (erythrocyte sedimentation rate [ESR]). Treatment response was evaluated 3-7 months after RTX. EBV load in baseline whole blood (WB) samples was determined using quantitative PCR. EBV DNA was detected in 16/35 (46 %) of the WB samples. In these 16 EBV-positive patients, the median viral load was 3.15 (2.68-4.00) log copies/ml. Good/moderate European League Against Rheumatism (EULAR) response was observed in 16/16 of the EBV DNA-positive vs 13/19 EBV DNA-negative patients, p = 0.022. Significant response (DAS28 change >1.2) was observed in 14/16 of the EBV DNA-positive vs 10/19 EBV DNA-negative patients, p = 0.035. The decline in DAS28 after RTX was 2.10 (1.03-4. 78) in the EBV DNA-positive vs 1.47 (-0.7-4.70) in the EBV DNA-negative patients, p = 0.13. EBV load at baseline significantly correlated with change in DAS28 after RTX (τB = -0.261, p = 0.042). Our results suggest that the presence of EBV genome in WB could serve as a predictive marker to RTX therapy in RA.

Myocardial Infarction after Rituximab Treatment for Rheumatoid Arthritis: Is there a Link?

Rituximab is an anti-CD20 monoclonal antibody often used in the treatment of rheumatoid arthritis (RA). Infusion reactions sometimes develop following rituximab administration. Delayed complications are rare. Acute coronary syndromes are listed as sideeffects of rituximab therapy. We report two cases of acute myocardial infarction following rituximab therapy for RA and review the literature regarding cardiac events in patients treated with rituximab. We would like to raise awareness of this possible complication in patients treated with rituximab.

Abatacept or tocilizumab after rituximab in rheumatoid arthritis? An exploratory study suggests non-response to rituximab is associated with persistently high IL-6 and better clinical response to IL-6 blocking therapy

ObjectivesTo evaluate the efficacy and safety of two different targeted approaches—abatacept or tocilizumab—after rituximab therapy in rheumatoid arthritis, and to explain observed difference in efficacy using blood and synovial studies...

FRI0202 Late onset neutropaenia in patients with rheumatoid arthritis after rituximab treatment

BackgroundLate onset neutropaenia (LON) is a recognised complication of rituximab (RTX) treatment in patients with haematological malignancies. There is increasing evidence that LON can also complicate B-cell depletion in patients...

THU0104 No expression of an alternative CD20 transcript variant in B cells from patients with rheumatoid arthritis

BackgroundTargeting B cells is an effective therapy in rheumatoid arthritis (RA). Rituximab (RTX) is a chimeric monoclonal antibody directed against the membrane CD20 protein present on B cells. Predictive factors...

Induced psoriasis after rituximab therapy for rheumatoid arthritis: a case report and review of the literature

Rituximab is a human/murine monoclonal antibody targeting the CD20 antigen on B-lymphocytes surface. Although it has been licensed for treatment of non-Hodgkin's lymphoma, nowadays it is also a novel therapy for autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Despite the increasing evidence regarding the safety and efficacy of rituximab in these conditions, many cutaneous adverse events have been reported. Here, we describe the case of a 69-year-old patient, affected by rheumatoid arthritis, who developed psoriatic lesions on her trunk and arms, three months after the second course of rituximab. Similar cases appearing in the literature will also be briefly mentioned.

Plantar pustulosis during rituximab therapy for rheumatoid arthritis

Plantar pustulosis during rituximab therapy for rheumatoid arthritis

Incidence of New-onset and Flare of Preexisting Psoriasis During Rituximab Therapy for Rheumatoid Arthritis: Data from the French AIR Registry

Psoriasis could be a paradoxical reaction to tumor necrosis factor-α antagonist therapy and it has been reported with rituximab therapy. Our objective was to assess the rates of new-onset and flare of preexisting psoriasis in patients taking rituximab for rheumatoid arthritis (RA). The nationwide multicenter prospective AutoImmunity and Rituximab (AIR) registry was set up in 2006 by the French Society for Rheumatology to collect data on patients taking rituximab for joint diseases. We identified patients with RA in the registry who had psoriasis listed as an adverse drug reaction, and we obtained additional information from their physicians if needed. We computed the incidence rates of new-onset and flare of preexisting psoriasis according to the rituximab exposure time. Among the 1927 patients in the registry with RA, 2 had new-onset and 5 had flare of preexisting psoriasis after a median followup of 39.2 weeks. Incidence rates were 1.04/1000 person-years (95% CI 0.13 to 3.8) for new-onset psoriasis and 2.6/1000 person-years (95% CI 0.84 to 6.1) for flare of preexisting psoriasis. Rituximab rechallenge in the 2 new-onset cases and in 2 flare cases was not followed by recurrence or exacerbation of psoriasis. Two of the 5 flare cases developed after discontinuation of methotrexate. Despite the small number of cases observed, leading to wide CI, the incidence rates in our study do not support a causative role of rituximab therapy in new-onset or flare of preexisting psoriasis in patients with RA.

Serum sickness and severe angioedema following rituximab therapy in RA

Dear Editor, Rituximab is being used frequently in rheumatology, particularly in patients with rheumatoid arthritis (RA), systemic vasculitis and systemic lupus erythematosus (SLE). It is a chimeric monoclonal antibody to CD20 antigen expressed on B-cell precursors and mature B-cells. Infusion-related reactions such as fever, rigors and chills are seen in up to 85% of treated patients.1 Reactions tend to be more severe during the first infusion with onset usually within 30–120 min.2 Fortunately, the risk of such a reaction falls significantly after the first episode.3 Serum sickness with the use of rituximab in 22 patients has been reported in the English literature so far.4-9 These patients had either a hematological malignancy or an autoimmune condition. Surprisingly, serum sickness has not been reported in RA. We describe the first reported case of serum sickness following rituximab infusion in a patient with RA. A 60-year-old woman with seropositive RA for 14 years, presented with a history of increased pain and swelling in the left ankle and right knee for one and a half months. She was unable to bear weight on the left ankle and used to limp. For the past 2 years, she had been taking a combination of intramuscular methotrexate 12.5 mg weekly, hydroxychloroquine 200 mg once daily, leflunomide 20 mg once daily and sulphasalazine 1000 mg twice daily. She had also received intra-articular injection of methylprednisolone into the left ankle and right knee in the previous month without much relief. One and a half years ago, the patient had received two doses of rituximab 500 mg each in another hospital without significant benefit. Examination revealed that the left ankle and right knee were swollen and tender. There was no deformity in any joint. The Disease Activity Score (DAS28) was 6.04. Investigations showed an Hb 10.6 g/dL, white blood cell count 6400/mm3, erythrocyte sedimentation rate of 81 mm/h, creatinine 0.9 mg/dL, rheumatoid factor 44.2 units/mL and anti-cyclic citrullinated protein 114 units/mL. Antinuclear antibody was negative. Since the patient was unable to tolerate higher doses of methotrexate because of severe nausea, and the disease was refractory, it was decided to explore biological therapy. As she had received a subtherapeutic dose of rituximab previously, we wondered if a full dose would have achieved the goal. Therefore, she was administered 1000 mg of rituximab intravenously over 4 h. She was premedicated with methylprednisolone 100 mg and pheniramine 25 mg. Six days later, she developed an erythematous, urticarial rash over the feet, hands and face. In addition, she developed pain and swelling in the shoulders (previously never involved) and high-grade fever up to 39°C. The right knee became acutely swollen. There was no hematuria. A diagnosis of serum sickness syndrome was made in view of the triad of fever, arthritis and erythematous rash following a drug exposure. The patient was treated with one intramuscular dose of methylprednisolone 80 mg and oral levocetirizine. There was resolution of symptoms within 3 days. Since the serum sickness subsided promptly, it was considered appropriate to go ahead with the second infusion of rituximab on day 15. After informed consent, the second dose of rituximab was carefully started, observing the standard protocol of premedication and slow rate of infusion. Within minutes, the patient developed swelling of lips and periorbital regions as well as choking sensation. Although blood pressure was normal, she developed tachycardia (100 beats/min). There was no wheezing in the chest. Rituximab infusion was abandoned and adrenaline 0.5 mL (1 : 1000) was injected intravenously. In the next hour the reaction subsided almost completely but heart rate increased to 125 beats/min before returning to normal. Electrocardiogram showed only sinus tachycardia. It is possible this was in keeping with a type 1 immunoglobulin E (IgE) mediated hypersensitivity reaction which should preclude any further use of the drug in this patient. Six months later, the patient was started on etanercept 50 mg subcutaneously per week in combination with weekly methotrexate. There was an excellent response with a DAS28 of 2.5 after 4 weeks. Serum sickness is a type 3 hypersensitivity reaction, which comprises a triad of fever, rash and arthralgias occurring in the appropriate timeframe, usually 10–14 days following primary antigen exposure or within a few days of secondary antigen exposure. Overt arthritis can develop with increased inflammatory markers and decreased C3 level.10 Rituximab causes this syndrome more in patients with autoimmune conditions than in hematological malignancies.9 Typically, it is a self-limiting illness and steroids provide rapid and complete relief of symptoms.11 Altered immune response to foreign antigens is involved in the pathogenesis. In RA, it may be under-recognized because of the clinical similarities between serum sickness and an exacerbation of RA. The lesson learnt from the present case is that rituximab should not be re-administered to those who develop an episode of rituximab-induced serum sickness.

The potential risk of infections during (prolonged) rituximab therapy in rheumatoid arthritis

Introduction: Biologicals are a fast expanding group of new drugs and rituximab (RTX) is one of them. Long-term efficacy and safety constantly need addressing as little is known about these factors. In rheumatoid arthritis, RTX it is used for active disease that is not responding to other therapies. Since RTX acts by depleting B-cells, concerns regarding the long-term safety of this drug have been raised.Areas covered: This review covers 10 manuscripts on RTX safety in rheumatoid arthritis published between January 2004 and July 2010.Expert opinion: In present literature RTX appears to be safe for up to five courses. In this review, important drawbacks of current research are discussed. Longer follow-up time is needed to make relevant conclusions on RTX safety with regard to infectious complications. Prolonged RTX therapy causes subsequent B-cell depletion. Eventually, plasma cells disappear, causing hypogammaglobulinemias and subsequent problems in immunity. The formation of new plasma cells is halted due to a lack of B-cells. Attention needs to be focused on the status of immunoglobulins and the role this plays in the occurrence of infections. Until a complete, long-term safety profile of RTX is available, it cannot be considered safe with regard to the incidence of infectious complications.

Swiss Consensus Statement: Recommendations for optimising re-treatment with MabThera® (rituximab) in rheumatoid arthritis

Rituximab is an effective treatment of rheumatoid arthritis (RA), which has been approved for the treatment of moderate to severe disease in patients with an inadequate response to anti-TNF therapies. Rituximab differs from other available biological agents for RA by way of its unique mode of action and unrivalled long dosing interval. The efficacy of rituximab subsides progressively over time and re-therapy is generally required to maintain long term disease control. The timing of re-treatment is currently not well established and varies widely in clinical practice. The present document is a concise recommendation regarding re-treatment with rituximab, based on validated outcomes such as the DAS28 and the EULAR response criteria. The recommendation was established through consensus between practitioners familiar with rituximab therapy in RA. Optimisation of the rituximab re-treatment schedule may improve patient outcomes and balance risks and benefits for the individual patient.

Disease activity–guided rituximab therapy in rheumatoid arthritis: The effects of re‐treatment in initial nonresponders versus initial responders

To explore the efficacy of re-treatment with rituximab in patients with rheumatoid arthritis (RA) who were initial nonresponders to treatment, and to evaluate the effects of rituximab in RA when re-treatment is given in a standardized way based on the Disease Activity Score in 28 joints (DAS28), according to the international consensus statement. Patients with RA who had a DAS28 of > or =3.2 received up to 3 courses of rituximab at intervals of at least 6 months, regardless of whether the patient had responded to the first course of treatment with rituximab. Of the 30 patients with RA who were included in the study, 26 could be evaluated for the efficacy of treatment after 6 months. Eighteen patients qualified for re-treatment at 6 months, 6 patients were re-treated at a later time point because of a disease relapse, and 2 other patients were not re-treated because they had low disease activity. Seven of the 24 patients who qualified for re-treatment had not exhibited clinical improvement after the first treatment course. These patients typically did not respond to subsequent courses of rituximab. Of interest, in the 17 patients who had exhibited a clinical response to the first course of rituximab, the second and third treatment courses resulted in European League Against Rheumatism responses similar to those observed after the first course, and no major relapses occurred before re-treatment. Rituximab re-treatment is not effective in patients who do not exhibit clinical improvement after the first treatment course, which is consistent with the notion that such patients represent a different pathogenetic subset of RA. Patients who initially responded to rituximab treatment experienced sustained benefit from DAS28-based systematic re-treatment according to the international consensus statement.

Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis

In rheumatoid arthritis (RA), B cell depletion occurs in all patients treated with rituximab, but the clinical responses to rituximab are variable. A highly sensitive assay was used to test the hypothesis that B cell depletion is variable, and that incomplete depletion leads to a poorer outcome. Sixty patients with active RA unresponsive to anti-tumor necrosis factor agents received two 1-gram infusions of rituximab. B cell numbers were measured by highly sensitive flow cytometry before and after each infusion and at 3-month intervals thereafter. A reduction in B cell levels below 0.0001x10(9)/liter was defined as complete depletion (compared with 0.05x10(9)/liter by conventional cytometry). Clinical responses were measured using the European League Against Rheumatism (EULAR) criteria. At 6 months, 92% of patients had a moderate-to-good clinical response according to the EULAR criteria. B cells were detected in 63% of patients after the first infusion of rituximab (median level 0.0009x10(9)/liter [range<0.0001-0.0015x10(9)/liter), and these patients had poorer clinical outcomes than patients with complete depletion. At 9 months, 82% of patients with complete depletion had a moderate-to- good EULAR response, compared with 43% of those with partial depletion (P=0.01). At 12 months, 59% of complete responders had a moderate-to-good EULAR response, compared with 21% of those with partial depletion (P=0.01). Patients in whom B cells were depleted only after the second infusion did no better than those in whom depletion was never complete and had poorer clinical outcomes than those in whom depletion was initially complete. This study is the first to show, using a highly sensitive analysis, that rituximab therapy is associated with variable diminution in B cell numbers. A lack of complete depletion of B cells after 1 infusion was associated with a poorer outcome.