Rituximab Associated Hypogammaglobulinemia in Autoimmune Disease.
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ABSTRACT: Objective
To evaluate the characteristics of patients with autoimmune disease with hypogammaglobulinemia following rituximab (RTX) and describe their long-term outcomes, including those who commenced immunoglobulin replacement therapy.Methods
Patients received RTX for autoimmune disease between 2003 and 2012 with immunoglobulin G (IgG) <7g/L were included in this retrospective series. Hypogammaglobulinemia was classified by nadir IgG subgroups of 5 to <7g/L (mild), 3 to <5g/L (moderate) and <3g/L (severe). Characteristics of patients were compared across subgroups and examined for factors associated with greater likelihood of long term hypogammaglobulinemia or immunoglobulin replacement.Results
142 patients were included; 101 (71%) had anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV), 18 (13%) systemic lupus erythematosus (SLE) and 23 (16%) other conditions. Mean follow-up was 97.2 months from first RTX. Hypogammaglobulinemia continued to be identified during long-term follow-up. Median time to IgG <5g/L was 22.5 months. Greater likelihood of moderate hypogammaglobulinemia (IgG <5g/L) and/or use of immunoglobulin replacement therapy at 60 months was observed in patients with prior cyclophosphamide exposure (odds ratio (OR) 3.60 [95% confidence interval (CI) 1.03 - 12.53], glucocorticoid use at 12 months [OR 7.48 (95% CI 1.28 - 43.55], lower nadir IgG within 12 months of RTX commencement [OR 0.68 (95% CI 0.51 - 0.90)] and female sex [OR 8.57 (95% CI 2.07 - 35.43)]. Immunoglobulin replacement was commenced in 29/142 (20%) and associated with reduction in infection rates, but not severe infection rates.Conclusion
Hypogammaglobulinemia continues to occur in long-term follow-up post-RTX. In patients with recurrent infections, immunoglobulin replacement reduced rates of non-severe infections.
SUBMITTER: Tieu J
PROVIDER: S-EPMC8149951 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH.MethodsClinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period.ResultsTwenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19-79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3-28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1-10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded.ConclusionIn patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH.Lay summaryAutoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome.
| S-EPMC7005655 | biostudies-literature
Project description:BackgroundX-linked lymphoproliferative disease (XLP) is a primary immunodeficiency presenting with a variety of clinical manifestations, the most common being dysgammaglobulinemia and B-cell lymphoma. The first gene causing XLP, when defective, was termed SH2D1A or SAP for signaling lymphocyte activation molecule (SLAM)-associated protein. The absence of SH2D1A leads to an overwhelming and uncontrolled TH1- shifted cytotoxic immune response, which might, at least in part, explain the severe clinical picture. A second gene, XIAP (X-linked inhibitor of apoptosis), was later identified.MethodsAn 8 year old Mexican boy was admitted in June 2008 for bronchopneumonia, with no previous history of recurrent or severe infections. He had a family history of a brother deceased at 7 years from fulminate hepatitis, who was diagnosed with agammaglobulinemia. A laboratory evaluation for primary immunodeficiency was made, including serum immunoglobulins: IgG 30 mg/dL, IgA <5 mg/dL IgM 8.6 mg/dL; and flow citometry for lymphocyte subpopulations: CD3+ 2590 mm3 (56%) CD4+ 1004 mm3 (42%), CD8+ 1267 mm3(53%) CD16/56 171mm3 (41%) CD19+ 1493 mm3 (35%). The patient was started on monthly intravenous gammaglobulin (IVIG) therapy. He was admitted in December 2008 with fever and severe abdominal pain; an exploratory laparotomy revealed a rectal-sigmoid tumor. The biopsy reported an atypical Burkitt lymphoma (Immunophenotype “B”: Bcl 2+, CD10+) with surgical margins negative for malignancy. Bone marrow aspirate and biopsy were negative for malignancy. In February 2009, management with chemotherapy was started with the diagnosis of Burkitt's lymphoma stage III. Patient received 6 courses of chemotherapy with complete response to induction; for consolidation, 4 doses of rituximab were given. PCR amplification and direct automated sequencing by the Sanger method was performed in both genes known to be responsible for XLP in chromosome X.ResultsA hemizygous splice-site deletion in SAP was found, in intron 2: c.187_201+10del25, which deletes exon 2 splice donor site, and is predicted to result in the skipping of exon 2, and thus in a truncated, nonfunctional protein. XIAP was also sequenced and no mutation was found.ConclusionsFinal diagnosis: XLP.The patient is currently in the program for hematopoietic stem-cell transplantation.
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