Emilio Besada

Characteristics of late onset neutropenia in rheumatologic patients treated with rituximab: a case review analysis from a single center

BACKGROUND Late onset neutropenia (LON) secondary to rituximab has been reported as an adverse event in the treatment of hematological malignancies but reports on autoimmune diseases are scarce. AIM To review the characteristics of LON in rheumatologic patients from a single center. DESIGN Retrospective case record study. METHODS Clinical and laboratory data since the introduction of rituximab in our clinic in 2006 were collected and analyzed retrospectively. LON was defined as an absolute neutrophil count <1.0 × 10(9)/l occurring 4 weeks after the last rituximab infusion. RESULTS LON was identified in eight patients (6% of all patients receiving rituximab). All patients had complicated and refractory disease and had been treated with a median of 4.5 different immunosuppressive drugs prior to rituximab. LON appeared after a median interval of 23 weeks with recovery of LON after a median of 6.5 days. Four patients had concomitant infection at the onset of neutropenia, when six patients had both low immunoglobulin M and immunoglobulin G. Six patients were rechallenged with rituximab without recurrence of LON. CONCLUSION The characteristics of LON after rituximab treatment in patients with autoimmune disease are comparable with experiences from hematological malignancies. LON seems to precede B-cell recovery implying a perturbation of the granulocyte homeostasis. LON with its rapid recovery does not seem to increase the risk for serious infection in contrast to the sustained hypogammaglobulinemia that may follow rituximab. The risk of LON recurrence after rechallenge is low.

Serum immunoglobulin levels and risk factors for hypogammaglobulinaemia during long-term maintenance therapy with rituximab in patients with granulomatosis with polyangiitis

OBJECTIVE Rituximab (RTX) is a B cell depleting agent used to induce and maintain remission in patients with granulomatosis with polyangiitis (GPA). As the development of hypogammaglobulinaemia in GPA patients on long-term RTX has not been addressed, the aim of this study was to investigate changes in immunoglobulin levels and risk factors for hypogammaglobulinaemia during long-term RTX maintenance therapy in GPA. METHODS We used a single-centre cohort study of 29 GPA patients who received a median total cumulative dose of CYC of 17 g and were treated with 2 g RTX followed by re-treatment with either 2 g once annually, 1 g biannually or a combination of both. Ig levels were measured before each RTX re-treatment and hypogammaglobulinaemia was defined as levels of total immunoglobulin <6 g/l. RESULTS During a median follow-up of 4 years, patients received a cumulative dose of 9 g RTX. While serum Ig levels decreased during RTX maintenance, the largest decrease occurred after the first infusion. Baseline Ig levels and the CYC cumulative dose predicted Ig levels, whereas the RTX cumulative dose did not. Eight patients (28%) discontinued RTX due to hypogammaglobulinaemia. Male gender [hazard ratio (HR) = 8.7, P = 0.044], kidney involvement (HR = 6.5, P = 0.083) and the 1 g biannual regimen (HR = 8.0, P = 0.024) increased the risk to discontinue RTX due to hypogammaglobulinaemia, whereas orbital-subglottic involvement (HR = 0.23, P = 0.080) decreased it. CONCLUSION Hypogammaglobulinaemia occurred in one-quarter of GPA patients during RTX maintenance, independent of the RTX cumulative dose. Male gender, kidney involvement and the 1 g biannual RTX regimen constitute risk factors for severe hypogammaglobulinaemia necessitating withdrawal of RTX.

Ultrasonographic resolution of the vessel wall oedema with modest clinical improvement in a large-vessel vasculitis patient treated with tocilizumab

We report a 63-year-old man with large-vessel giant cell arteritis with affection of the aorta in its thoracal descendens and abdominal segments, both axillar arteries and the left carotid artery. The diagnosis was confirmed with positive biopsy of the temporal artery. The patient was treated with prednisolone at first and thereafter with methotrexate. Due to a moderate clinical response, tocilizumab at a dose of 8 mg/kg was added 8 weeks after diagnosis. The patient did not improve clinically, and the prednisolone dose could not be tapered rapidly as previously reported in small case series. Nevertheless, the wall oedema determined by ultrasonography in both axillar and left carotid arteries almost disappeared 2 months after tocilizumab initiation. Two months after the last tocilizumab, the patient relapsed clinically. Tocilizumab seems to be an effective therapy with faster resolution of the vessel wall oedema determined by ultrasonography by suppressing Th17-cell activity. But the clinical improvement in our patient has been moderate and short-lived due to persistent Th1 cells activity.

Should rheumatoid factor in rheumatoid arthritis be sent to Davy Jones's Locker?

This article reviews the characteristics and weaknesses of the rheumatoid factor (RF) assay compared with anti-citrullinated peptide antibody (ACPA) testing in the work-up of patients with synovitis. This should lead physicians to change their ordering habits and replace RF by ACPA. For RA diagnosis, good clinical judgement based on clinical history, physical examination and routine laboratory work exceeds the value of RF and ACPA assays. In settings of both low and high pretest probability, the added value of each of these assays is low. In cases with intermediate probability, ACPA assays are superior to immunoglobulin (Ig)M-RF because of their higher specificity, and they should be the first choice in a RA diagnostic work-up. Dual testing brings few additional advantages and increases costs significantly. ACPA and IgM-RF are both imperfect tests; around 30% of patients with manifest RA will test negative in both assays and therefore caution needs to be exercised when interpreting negative results. Since 2009, the anti-cyclic citrullinated peptide (anti-CCP) antibody assay has been the only assay available at our institution for RA work-up, with IgM-RF available on a case-by-case basis for non-RA diseases. This has led to a 70% reduction in RF assays performed annually.

Infection risks during longterm rituximab therapy change over time

To the Editor: In the recent report from the German Registry of Autoimmune Disease (GRAID), Roll, et al showed that rituximab (RTX) was well tolerated with good clinical efficacy in patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV)1. However, we would like to share some concerns about their statement that RTX does not increase the rate for infections. The rate for severe infection in our institution is … Address correspondence to Dr. E. Besada, Rheumatology Department, University Hospital North Norway, Postboks 14, 9038 Tromso, Norway. E-mail: emilio.besada{at}unn.no

Imported case of visceral leishmaniasis presenting as pancytopenia in a Norwegian patient treated with methotrexate and etanercept for psoriasis arthritis

We report a case of visceral leishmaniasis in a patient from northern Norway with psoriatic arthritis treated with a combination of etanercept and methotrexate. The patient resided extensively in southern Spain, a zone endemic for leishmania.

Risk Factors and Adverse Events Poorly Predict Infections and Hypogammaglobulinemia in Granulomatosis with Polyangiitis Patients Receiving Rituximab.

Background. 29 GPA patients from the Northern Norway vasculitis disease registry received rituximab (RTX) induction and maintenance. 24% and 31% had, respectively, severe and chronic infections while 45% had hypogammaglobulinemia and 28% discontinued RTX due to hypogammaglobulinemia. The aim of the study was to examine how known predictors and adverse events interacted with adverse events using structural statistical methods. Methods. Five predictors (age, cyclophosphamide, total Ig and CD4/CD8 ratio prior RTX, and type of RTX maintenance regimen) and 4 adverse events (severe and chronic infections, hypogammaglobulinemia, and RTX discontinuation) were modeled in principal component and redundancy analyses. Results. The 5 predictors explained 51% of the variance of the GPA cohort. Models including cyclophosphamide exposure and total Ig level predicted best adverse events. However total Ig level has low R squared. The 2 best combinations of adverse events explained 13% of the variance of the predictors and adverse events. Only chronic infections were associated with combination of all adverse events (P = 0.014). Hypogammaglobulinemia did not seem associated with the other adverse events. Conclusions. Traditional risk factors for infections and hypogammaglobulinemia seemed to poorly predict adverse events in our GPA cohort.

Staphylococcus Aureus carriage and long-term Rituximab treatment for Granulomatosis with polyangiitis

Objective. Chronic nasal carriage of Staphylococcus aureus (SA) increases the risk of relapse while Rituximab (RTX) is an effective agent for inducing and maintaining remission in patients with Granulomatosis with polyangiitis (GPA). We investigated whether B cell depletion and hypogammaglobulinemia that occur during RTX treatment increase the risk of chronic SA nasal carriage and subsequent disease flares, in GPA patients on long-term RTX maintenance therapy. Methods. Retrospective cohort study from a disease registry involving 29 GPA patients receiving RTX maintenance (median RTX dose of 9 g) during a median period of 49 months. Nasal swabs were collected prior and during RTX for a median of 3 and 9 swabs respectively. Persistent SA nasal carriage was defined with the presence of SA in more than 75% of nasal swabs. Results. SA nasal carriage did not change during RTX (p = 0.297). However, the rate of positive nasal swabs in GPA patients with transient SA nasal carriage during RTX maintenance increased from 0 prior RTX to 0.42 during RTX (p = 0.017). Persistent SA nasal carriage did not increase the risk of relapses (p = 0.844), of hypogammaglobulinemia (p = 0.122) and of severe infections (p = 0.144), but reduced the risk of chronic infections (p = 0.044). Change in SA carriage status during RTX did not influence the risk of relapses (p = 0.756), hypogammaglobulinamia (p = 0.474) and infections, either severe (p = 0.913) or chronic (p = 0.121). Conclusion. Long-term RTX maintenance therapy in GPA patients did not significantly influence SA nasal carriage status. Persistent SA carriage during long-term RTX treatment did not seem to increase the risk of relapses, but seemed to decrease the risk of hypogammaglobulinemia associated chronic infections.

Potential patient benefit of a subcutaneous formulation of tocilizumab for the treatment of rheumatoid arthritis: a critical review.

Treatment of rheumatoid arthritis (RA) was revolutionized during the last decade with the development of new biologic disease-modifying anti-rheumatic drugs (DMARDs) enabling the targeting of immune cells and cytokines other than tumor necrosis factor (TNF). Subcutaneous formulations of the newer biologic DMARDs facilitate not only patients’ emancipation from the hospital, but reduce both societal and medical costs. Intravenous tocilizumab (TCZ) in RA has an efficacy and safety profile similar to anti-TNF in both the short and long-term. However, TCZ can be administered in monotherapy without loss of efficacy when patients do not tolerate methotrexate or synthetic DMARDs. TCZ is consistently found superior to methotrexate and possibly superior to adalimumab in monotherapy in randomized controlled trials. Subcutaneous administration of TCZ is as effective and safe as its intravenous administration in RA patients during the first year of treatment. Similar to intravenous TCZ, patients’ weight and possibly previous use of anti-TNF influence the efficacy of subcutaneous TCZ. Additionally, combination with synthetic DMARDs seems to expose RA patients to more adverse events independently of its administration route. Pharmacokinetics of different administration routes could potentially lead to differences in efficacy, adverse events, and auto-immunogenicity. The concentration of free TCZ before new TCZ dose (C trough) is higher in the subcutaneous route, while the maximal concentration of free TCZ is higher in the intravenous route. The subcutaneous dosages of TCZ 162 mg every week, and every 2 weeks in RA patients with low body weight (<60 kg) work well. Nevertheless, dosage and intervals of subcutaneous TCZ administration could be adjusted during the course of treatment since 80% of non-Japanese RA patients with usually higher body weight achieved similar efficacy with the low TCZ dosage in combination with a synthetic DMARD. Patients want effective, easy-to-administer therapy with sustained prolonged efficacy without the need of polypharmacy and with minimal to no side effects. Subcutaneous TCZ in RA patients in monotherapy seems to live up to patients’ expectations.

Routine Pneumocystis Pneumonia Prophylaxis in Patients Treated With Rituximab

journal.publications.chestnet.org Figure 1. Proposed relationship among pulmonary infl ammation, systemic infl ammation, and COPDrelated comorbidities. *Statins have been shown to attenuate both pulmonary and systemic infl ammation through their effects on the innate immune response and NF k B/STAT3-mediated infl ammatory pathways. CRP 5 C-reactive protein; ETS 5 environmental tobacco smoke; M F 5 macrophage; NF k B 5 nuclear factor k B; PMN 5 polymorphic neutrophil; SAD 5 small airways disease; STAT3 5 signal transducer and activator of transcription 3; TNF a 5 tumor necrosis factora .