CD4 cell count and CD4/CD8 ratio increase during rituximab maintenance in granulomatosis with polyangiitis patients.

INTRODUCTION: Rituximab (RTX) is a B cell-depleting agent approved for the treatment of granulomatosis with polyangiitis (GPA). RTX reduces antibody producing precursor plasma cells and inhibits B and T cells interaction. Infections related to T cell immunodeficiency are not infrequent during RTX treatment. Our study investigated CD4 cell count and CD4/CD8 ratio in GPA patients during the first two years of long-term RTX treatment. METHODS: A single centre cohort study of 35 patients who received median total cumulative dose of cyclophosphamide (CYC) of 15 g and were treated with RTX 2 g followed by retreatment with either 2 g once annually or 1 g biannually. Serum levels of total immunoglobulin (Ig) and lymphocytes subsets were recorded at RTX initiation and at 3, 6, 12, 18 and 24 months. Low CD4 count and inverted CD4/CD8 ratio were defined as CD4 < 0.3 × 10(9)/l and ratio < 1. RESULTS: The CD4 cell count and CD4/CD8 ratio decreased slightly following the initial RTX treatment and then increased gradually during maintenance treatment. While the proportion of patients with low CD4 cell count decreased from 43% at baseline to 18% at 24 months, the ratio remained inverted in 40%. Oral daily prednisolone dose at baseline, CYC exposure and the maintenance regimen did not influence the CD4 cell count and ratio. Being older (p = 0.012) and having a higher CRP (p = 0.044) and ESR (p = 0.024) at baseline significantly increased the risk of inverted CD4/CD8 ratio at 24 months. Inverted ratio at baseline associated with lower total Ig levels during the study. CONCLUSIONS: Overall, the CD4 and CD4/CD8 ratio increased during maintenance RTX therapy in GPA with no discernible impact of other immunosuppressive therapy. However the increase in CD4 was not followed by an increase in the CD4/CD8 ratio, especially in older patients. Inverted CD4/CD8 ratio associated with lower Ig levels, suggesting a more profound B cell depleting effect of RTX with a relative increase in CD8+ lymphocytes.

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.

Low immunoglobulin levels increase the risk of severe hypogammaglobulinemia in granulomatosis with polyangiitis patients receiving rituximab.

BACKGROUND: Randomized controlled trials and retrospective studies in ANCA-associated vasculitis (AAV) concurred that rituximab (RTX) is effective to induce and maintain remission. Infections and hypogammaglobulinemia during RTX were usually infrequent and uncomplicated. But in the Tromsø study cohort, 45% of patients with granulomatosis with polyangiitis (GPA) developed hypogammaglobulinemia during RTX maintenance leading to its discontinuation in 62%. METHODS: To explain these differences in outcome when using RTX in AAV to maintain remission, we used statistical structural methods to compare the Tromsø study cohort with other published cohorts. RESULTS: GPA patients' characteristics of the Tromsø study cohort were not so different compared with other cohorts. Rates of hypogammaglobulinemia and discontinuation of RTX seemed closely related to the cut-off used and to the levels of immunoglobulin (Ig) at baseline. Combination of low IgG serum levels at baseline (7.7 g/L) and low cut-off to define hypogammaglobulinemia in the Tromsø study cohort explained the high rate of hypogammaglobulinemia and discontinuation of RTX. CONCLUSIONS: Patients' characteristics in the Tromsø study cohort were not skewed, apart from IgG levels. Low IgG level at baseline seemed to contribute the most to hypogammaglobulinemia and its complications.

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.

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.

Long-term efficacy and safety of pre-emptive maintenance therapy with rituximab in granulomatosis with polyangiitis: results from a single centre.

OBJECTIVE: Rituximab (RTX) is an anti-CD20 antibody used successfully in granulomatosis with polyangiitis (GPA) for induction and maintenance of remission. Our study aims to evaluate the long-term efficacy and safety of chronic pre-emptive RTX therapy in GPA. METHODS: Retrospective study of 35 GPA patients treated with RTX between April 2004 and September 2011 for active disease and maintenance. RTX was initiated as two 1 g infusions 2 weeks apart and thereafter 2 g of RTX was readministered annually. Patients were followed for 47 (2-88) months. They received a median RTX dose of 8 g (2-13) over 5 (1-10) rounds. RESULTS: All patients had a clinical response, but nine relapses were recorded (flare rate of 6.6/100 patient-years). At last visit, 13 patients (37%) had discontinued RTX mainly due to hypogammaglobulinaemia (57%). Nine patients (26%) had severe infections (infection rate of 6.6/100 patient-years) and 10 patients (29%) had chronic infections. Risks factors for severe infections are a high cumulative dose of CYC, low CD4 cell count and a significant drop in total immunoglobulins after the first RTX round. Risks factors for chronic infections are low IgG level during RTX maintenance and possibly the cumulative RTX dose. CONCLUSION: Long-term pre-emptive RTX maintenance was efficacious in reducing the risk for relapse but was discontinued in one-third of the patients. The patients' net state of immunodeficiency under RTX changes over time as low immunoglobulin serum levels increased the risk for infections.

Should Pneumocystis jiroveci prophylaxis be recommended with Rituximab treatment in ANCA-associated vasculitis?

Reports in haematology, transplantation medicine and rheumatology indicate that Rituximab, a B cell depleting therapy, increases the risk for Pneumocystis jiroveci pneumopathy. Patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis have an increased incidence of P. jiroveci pneumopathy compared to other autoimmune diseases and Rituximab is often used to induce and maintain remission. Herein, we present a case of a patient with granulomatosis with polyangiitis treated with Rituximab for relapse that developed P. jiroveci pneumopathy 3 months after and we review the relevant literature to assess P. jiroveci pneumopathy incidence and risks factors under Rituximab. We also discuss whether P. jiroveci screening before Rituximab and P. jiroveci pneumopathy prophylaxis under Rituximab are indicated. P. jiroveci colonisation is found in 25 % of patients with autoimmune diseases. However, the association between colonisation and P. jiroveci pneumopathy development is not very strong. P. jiroveci pneumopathy incidence in ANCA-associated vasculitis patients treated with Rituximab is found to be 1.2 %. Therefore, evidence and practice do not support the use of P. jiroveci pneumopathy chemoprophylaxis in all ANCA-associated vasculitis patients receiving Rituximab. CD4 cell count cut-off does not work well in patients treated with Rituximab as it does not reflect T cell impairment following B cell depletion. To help stratify the risk of both colonisation and P. jiroveci pneumopathy development, assessment of the patient's net state of immunodeficiency before administering Rituximab-including age, renal or lung involvement, previous infections due to T cell dysfunction, blood tests (lymphocytopenia, low CD4 cell count) and concomitant therapy-is warranted.

Successful treatment with bortezomib in type-1 cryoglobulinemic vasculitis patient after rituximab failure: a case report and literature review.

Type-1 cryoglobulinemic vasculitis (CV) and mixed CV differ in their pathophysiology, clinical expression and treatment response. We report one patient with type-1 cryoglobulinemic vasculitis and skin ulcers that had remained active despite treatment with a variety of immunomodulating drugs including rituximab. The patient had a past medical history of non-Hodgkin lymphoma 10 years after CV onset for which she went into complete remission. The patient developed subsequent hematological anomalies in the serum and in the bone marrow without a definite diagnosis of myeloma. The patient finally went into clinical remission of her cryoglobulinemic vasculitis after treatment with bortezomib and dexamethasone. But she did not achieve an immunological remission and still had positive cryoglobulinemia and serum kappa-type free light chains. This suggests that bortezomib, a proteasome inhibitor that inhibits angiogenesis and production of paraproteins, is a promising treatment in type-1 cryoglobulinemic vasculitis.

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.

Sustained hypogammaglobulinemia under rituximab maintenance therapy could increase the risk for serious infections: a report of two cases.

We report two patients with granulomatosis with polyangiitis in remission with rituximab maintenance therapy with sustained hypogammaglobulinemia. Both patients had serious infections and were admitted to the intensive therapy unit. The patients had at least low IgM levels prior to the initiation of rituximab. They received cyclophosphamide and prednisolone at induction and at maintenance. They had lung affection, low level of both IgM and IgG and a cumulative dose of rituximab over 7 g at the time of the severe infection. Our patients have features similar to common variable immunodeficiency patients, and therefore prolonged very low levels of immunoglobulins could heighten the risk for severe infections.

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.