BACKGROUND:

Rituximab is a selective, B-cell depleting, biologic agent for treating refractory rheumatoid arthritis (RA). It is a chimeric monoclonal antibody targeted against CD 20 that is promoted as therapy for patients who fail to respond to other biologics. There is evidence to suggest that rituximab is effective and well tolerated when used in combination with methotrexate for RA.

OBJECTIVES:

To evaluate the benefits and harms of rituximab for the treatment of RA.

SEARCH METHODS:

We conducted a search (until January 2014) in electronic databases (The Cochrane Library, MEDLINE, EMBASE, CINAHL, Web of Science), clinical trials registries, and websites of regulatory agencies. Reference lists from comprehensive reviews were also screened.

SELECTION CRITERIA:

All controlled trials comparing treatment with rituximab as monotherapy or in combination with any disease modifying anti-rheumatic drug (DMARD) (traditional or biologic) versus placebo or other DMARD (traditional or biologic) in adult patients with active RA.

DATA COLLECTION AND ANALYSIS:

Two review authors independently assessed the risk of bias and abstracted data from each study.

MAIN RESULTS:

We included eight studies with 2720 patients. For six studies selection bias could not be evaluated and two studies were considered to have low risk of bias. The level of evidence ranged from low to high, but was rated as moderate for most outcomes. We have prioritised reporting of rituximab (two 1000 mg doses) in combination with methotrexate since this is the approved dose and most commonly used combination. We also reported data on other combinations and doses as supplementary information in the results section of the review.American College of Rheumatology (ACR) 50 response rates were statistically significantly improved with rituximab (two 1000 mg doses) in combination with methotrexate compared with methotrexate alone at 24 to 104 weeks. The RR for achieving an ACR 50 at 24 weeks was 3.3 (95% CI 2.3 to 4.6); 29% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate achieved the ACR 50 compared to 9% of controls. The absolute treatment benefit (ATB) was 21% (95% CI 16% to 25%) with a number needed to treat (NNT) of 6 (95% CI 4 to 9).At 52 weeks, the RR for achieving clinical remission (Disease Activity Score (DAS) 28 joints < 2.6) with rituximab (two 1000 mg doses) in combination with methotrexate compared with methotrexate monotherapy was 2.4 (95% CI 1.7 to 3.5); 22% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate achieved clinical remission compared to 11% of controls. The ATB was 11% (95% CI 2% to 20%) with a NNT of 7 (95% CI 4 to 13).At 24 weeks, the RR for achieving a clinically meaningful improvement (CMI) in the Health Assessment Questionnaire (HAQ) (> 0.22) for patients receiving rituximab combined with methotrexate compared to patients on methotrexate alone was 1.6 (95% CI 1.2 to 2.1). The ATB was 24% (95% CI 12% to 36%) with an NNT of 5 (95% CI 3 to 13). At 104 weeks, the RR for achieving a CMI in HAQ (> 0.22) was 1.4 (95% CI 1.3 to 1.6). The ATB was 24% (95% CI 16% to 31%) with a NNT of 5 (95% CI 3 to 7).At 24 weeks, the RR for preventing radiographic progression in patients receiving rituximab (two 1000 mg doses) in combination with methotrexate was 1.2 (95% CI 1.0 to 1.4) compared to methotrexate alone; 70% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate had no radiographic progression compared to 59% of controls. The ATB was 11% (95% CI 2% to 19%) and the NNT was 10 (95% CI 5 to 57). Similar benefits were observed at 52 to 56 weeks and 104 weeks.Statistically significantly more patients achieved a CMI on the physical and mental components of the quality of life, measured by the Short Form (SF)-36, in the rituximab (two 1000 mg doses) in combination with methotrexate-treated group compared with methotrexate alone at 24 to 52 weeks (RR 2.0, 95% CI 1.1 to 3.4; NNT 4, 95% CI 3 to 8 and RR 1.4, 95% CI 1.1 to 1.9; NNT 8, 95% CI 5 to 19, respectively); 34 and 13 more patients out of 100 showed an improvement in the physical component of the quality of life measure compared to methotrexate alone (95% CI 5% to 84%; 95% CI 7% to 8%, respectively).There was no evidence of a statistically significant difference in the rates of withdrawals because of adverse events or for other reasons (that is, withdrawal of consent, violation, administrative, failure to return) in either group. However, statistically significantly more people receiving the control drug withdrew from the study compared to those receiving rituximab (two 1000 mg doses) in combination with methotrexate at all times (RR 0.40, 95% CI 0.32 to 0.50; RR 0.61, 95% CI 0.40 to 0.91; RR 0.48, 95% CI 0.28 to 0.82; RR 0.58, 95% CI 0.45 to 0.75, respectively). At 104 weeks, 37% withdrew from the control group and 20% withdrew from the rituximab (two 1000 mg doses) in combination with methotrexate group. The absolute risk difference (ARD) was -20% (95% CI -34% to -5%) with a number needed to harm (NNH) of 7 (95% CI 5 to 11).A greater proportion of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate developed adverse events after their first infusion compared to those receiving methotrexate monotherapy and placebo infusions (RR 1.6, 95% CI 1.3 to 1.9); 26% of those taking rituximab plus methotrexate reported more events associated with their first infusion compared to 16% of those on the control regimen with an ARD of 9% (95% CI 5% to 13%) and a NNH of 11 (95% CI 21 to 8). However, no statistically significant differences were noted in the rates of serious adverse events.

AUTHORS' CONCLUSIONS:

Evidence from eight studies suggests that rituximab (two 1000 mg doses) in combination with methotrexate is significantly more efficacious than methotrexate alone for improving the symptoms of RA and preventing disease progression.

OBJECTIVE:

To review published literature evaluating the use of rituximab for treatment of acquired hemophilia.

DATA SOURCES:

An English-language literature search was conducted using MEDLINE (1966-January 2006). References of identified articles were subsequently reviewed for additional data. Search terms included rituximab, acquired hemophilia, and inhibitors.

DATA SYNTHESIS:

Available data suggest that B-cell depletion by rituximab in patients with acquired hemophilia may contribute to the eradication of inhibitors to coagulation factors. B-cells have been shown to be essential in the development of autoimmunity or an acquired immune response. Beneficial effects of rituximab, after failure of established therapies, have been reported in case reports and one small, open-label trial.

CONCLUSIONS:

Although data are limited, administration of rituximab appears to be an effective option for treatment of patients with acquired hemophilia after established therapies have failed. Patients given rituximab experienced cessation of recurrent bleeding, normalization of factor VIII activity, and eradication of inhibitors. A complete response to rituximab (undetectable inhibitors, normalization of factor levels) generally occurred several weeks to months after initiation of therapy.

Rituximab es un anticuerpo monoclonal quimérico dirigido contra los linfocitos B CD20 positivos. Está indicado en aquellos pacientes con AR activa con inadecuada respuesta a una o más agentes anti-TNFα. Si bien puede utilizarse como monoterapia, la asociación con MTX aumenta su eficacia. Dos dosis de 1 gramo EV separadas por un intervalo de 15 días permiten obtener una respuesta clínica significativa (ACR 70) en un porcentaje mayor de pacientes.Los pacientes deber ser premedicados con metilprednisolona EV y eventualmente paracetamol y antihistamínicos por vía oral. La mayoría de los pacientes requieren reinfusión a las 24 semanas, sin embargo eso debe ser evaluado de acuerdo a la respuesta clínica. Rituximab NO debe ser utilizado en pacientes con infecciones activas, hepatitis B y en aquellos con antecedentes de hipersensibilidad a la droga. Abatacept es una proteína humana recombinante que bloquea la señal co-estimuladora del linfocito T. Está indicado en pacientes con AR activa que no han respondido a MTX, otra DMAR o a agentes anti-TNFα. Se utiliza por administración EV en 30 minutos con dosis ajustables al peso corporal y la asociación con MTX aumenta la respuesta clínica. Luego de una dosis de carga inicial cada 15 días, el intervalode administración es mensual. Abatacept NO debe ser utilizado en pacientes con infecciones activas, en tratamiento concomitante con agentes anti-TNFα o en aquellos con antecedentes de hipersensibilidad a la droga.Se recomienda el uso cuidadoso y monitoreo estricto de pacientes con antecedentes de enfermedad pulmonar obstructiva crónica (EPOC).

BACKGROUND:

Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting.

METHODS:

In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845.

FINDINGS:

Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment.

INTERPRETATION:

Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients.

FUNDING:

Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc.

BACKGROUND:

Pneumocystis pneumonia (PcP) is an opportunistic fungal infection. Although T-cell immunity is classically related to Pneumocystis defense, recent data support roles for B lymphocytes in the development of PcP in animals, and we have observed several cases of PcP in patients receiving rituximab. These observations prompted a systematic review of our experience to define the spectrum of clinical presentations in which PcP has occurred in the setting of rituximab therapy.

METHODS:

Using a computer-based search, we reviewed the records of patients who received rituximab and developed PcP at Mayo Clinic Rochester over the years 1998 to 2011 to establish the underlying conditions, clinical course, possible risk factors, and potential association between this drug and the development of PcP.

RESULTS:

Over this period, 30 patients developed PcP during treatment with rituximab. The underlying diseases included hematologic malignancies in 90% of cases. Glucocorticoids were used in 73% of these patients, under different chemotherapeutic regimens. Three patients (10%) developed PcP in the setting of rituximab without concomitant chemotherapy or significant glucocorticoid exposure. Of these 30 patients, 88% developed acute hypoxemic respiratory failure and 53% required ICU admission. The clinical course was fatal in 30%.

CONCLUSION:

PcP can occur in association with rituximab, with the majority of cases having also received cytotoxic chemotherapy or significant doses of glucocorticoids. The clinical course of cases of PcP in patients treated with rituximab can be quite fulminant, with significant mortality. Primary prophylaxis should be considered in patients at risk, and secondary prophylaxis provided unless immune reconstitution is well assured.

BACKGROUND:

This is an update of the Cochrane review "Rituximab for relapsing-remitting multiple sclerosis" (first published in The Cochrane Library 2011, Issue 12).
More than 80% of individuals with multiple sclerosis (MS) experience a relapsing-remitting disease course. Approximately 10 years after disease onset, an estimated 50% of individuals with relapsing-remitting MS (RRMS) convert to secondary progressive MS. MS causes a major socioeconomic burden for the individual patient and for society. Effective treatment that reduces relapse frequency and prevents progression could impact both costs and quality of life and help to reduce the socioeconomic burden of MS. Alternative and more effective MS treatments with new modes of action and good safety are needed to expand the current treatment repertoire. It has been shown that B lymphocytes are involved in the pathophysiology of MS and rituximab lyses B-cells via complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Current clinical trials are evaluating the role of rituximab as a B-cell depletion therapy in the treatment of RRMS.

OBJECTIVES:

The safety and effectiveness of rituximab, as monotherapy or combination therapy, versus placebo or approved disease-modifying drugs (DMDs) (interferon-β (IFN-β), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab) to reduce disease activity for people with RRMS were assessed.

SEARCH METHODS:

The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (9 August 2013). We checked the references in identified trials and manually searched the reports (2004 to August 2013) from neurological associations and MS societies in Europe and America. We also communicated with researchers who were participating in trials on rituximab and contacted Genentech, BiogenIdec and Roche.

SELECTION CRITERIA:

All randomised, double-blind, controlled parallel group clinical trials with a length of follow-up equal to or greater than one year evaluating rituximab, as monotherapy or combination therapy, versus placebo or approved DMDs for patients with RRMS without restrictions regarding dosage, administration frequency and duration of treatment.

DATA COLLECTION AND ANALYSIS:

We used the standard methodological procedures of The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. Principal investigators of included studies were contacted for additional data or confirmation of data.

MAIN RESULTS:

One trial involving 104 adult RRMS patients with an entry score ≤ 5.0 on the Expanded Disability Status Scale (EDSS) and at least one relapse during the preceding year was included. This trial evaluated rituximab as monotherapy versus placebo, with a single course of 1000 mg intravenous rituximab (on day 1 and day 15). A significant attrition bias was found at week 48 (24.0%). Patients receiving rituximab had a significant reduction in total number of gadolinium-enhancing lesions at week 24 (mean number 0.5 versus 5.5; relative reduction 91%) and in annualised rate of relapse at week 24 (0.37 versus 0.84) but not at week 48 (0.37 versus 0.72). Disability progression was not included as an outcome in this trial. More patients in the rituximab group had adverse events within the 24 hours after the first infusion (78.3% versus 40.0%), such as chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation, pharyngolaryngeal pain, and most were mild-to-moderate events (92.6%). The most common infection-associated adverse events (> 10% in the rituximab group) were nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. Among them, only urinary tract infections (14.5% versus 8.6%) and sinusitis (13.0% versus 8.6%) were more common in the rituximab group. One ongoing trial was identified.

AUTHORS' CONCLUSIONS:

There is not sufficient evidence to support the use of rituximab as a disease-modifying therapy for RRMS because only one RCT was included. The quality of the study was limited due to high attrition bias, the small number of participants, and short follow-up. The beneficial effects of rituximab for RRMS remain inconclusive. However, short-term treatment with a single course of rituximab was safe for most patients with RRMS. Mild-to-moderate infusion-associated adverse events were common, as well as nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. The potential benefits of rituximab for treating RRMS need to be evaluated in large-scale studies that are of high quality along with long-term safety.

OBJECTIVE:

To review published literature using rituximab for treatment of refractory rheumatoid arthritis (RA).

DATA SOURCES:

An English-language literature search was conducted using MEDLINE (1966-May 2005) and EMBASE (1980-May 2005). References of identified articles were subsequently reviewed for additional data.

DATA SYNTHESIS:

Evidence suggests that B lymphocyte depletion in patients suffering from refractory RA may be a key component in the interruption of the disease pathogenesis. Successful depletion of B lymphocytes with rituximab in patients with RA has been reported in case reports, open-label pilot studies, and a randomized, double-blind, placebo-controlled trial.

CONCLUSIONS:

Based on the limited published data, rituximab, when used in combination with other agents (ie, cyclophosphamide or methotrexate), appears to be a reasonable treatment option for refractory RA. However, additional controlled trials need to be conducted to further define optimal dosing, response rates, comparative long-term efficacy, and RA treatment algorithm placement of rituximab in this patient population.

CRD SUMMARY:

This well-conducted review found that rituximab is generally well tolerated and may improve response in people with low-grade lymphoma. There were insufficient data on long-term outcomes or people with histological subtypes other than low-grade lymphoma. CHOP chemotherapy plus rituximab appears to improve response and survival more than CHOP alone in people with diffuse large B cell lymphoma.

OBJECTIVES:

The aim of this study was to evaluate the efficacy and safety of rituximab and tocilizumab compared with adalimumab, etanercept, and infliximab, in patients with rheumatoid arthritis not responding to first-line treatment, and to compare the efficacy and safety of rituximab versus tocilizumab in patients not responding to anti-tumor necrosis factor α (anti-TNF) therapy.

METHODS:

A literature search of randomized controlled trials, controlled clinical trials, and systematic reviews was performed to evaluate efficacy and safety of rituximab and tocilizumab.

RESULTS:

Twenty-four RCTs were included in this systematic review with 6,357 participants; 3,450 treated with biological DMARD and 2,907 with standard care. In patients not responding to first-line treatment, rituximab shows lower response rate in at least 50 percent improvement in the American College of Rheumatology criteria (ACR50) and ACR70 compared with etanercept, at 6 months of follow-up. Tocilizumab shows higher ACR70 response rate compared with infliximab, at the same follow-up time. Other results showed no significant differences. Indirect comparisons between rituximab and tocilizumab in patients not responding for at least one anti-TNF, shows higher ACR20 response rate for tocilizumab at 6 months of follow-up. Regarding safety, adalimumab and etanercept were associated with significant fewer withdrawals due to adverse events compared with infliximab.

CONCLUSIONS:

Considering efficacy, safety, and the availability of 3 anti-TNFs in the National Medicines Formulary (adalimumab, etanercept, and infliximab), it seems appropriate to remove infliximab from the coverage, and introduce tocilizumab for patients not responding for at least one anti-TNF.

BACKGROUND:

The general consensus is that for patients with EGPA with poor prognosis, intensive therapy with both GC and CF is indicated. The maintenance of remission is made with GC and AZA. A considerable number of patients with EGPA are refractory to first line therapy, experience dose-limiting side effects or relapse. In clinical trials, RTX was effective for the treatment of ANCA-associated vasculitis. However, patients with a diagnosis of EGPA were not included.

OBJECTIVE:

to review and analyze the published literature regarding the use of RTX in the treatment of EGPA.

METHODS:

The literature search was performed in MEDLINE and LILACS from 1965 and 1986 respectively until february 2014.

RESULTS:

27 patients were included. RTX treatment was due to refractory disease (n=20), relapse (n=5) and with newly diagnosed (n=2). The affected organs were the lungs, peripheral nervous system, kidney and the eyes. Sixteen patients had clinical remission and 8 patients had clinical response.

CONCLUSIONS:

RTX was effective and well tolerated for the treatment of EGPA.