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The European Respiratory Journal Jun 2023Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy.
METHODS
In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety.
FINDINGS
Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group.
INTERPRETATION
Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.
Topics: Humans; Rituximab; Mycophenolic Acid; Immunosuppressive Agents; Lung; Treatment Outcome; Lung Diseases, Interstitial; Idiopathic Interstitial Pneumonias; Double-Blind Method
PubMed: 37230499
DOI: 10.1183/13993003.02071-2022 -
The New England Journal of Medicine Jun 2023In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil.
METHODS
In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the , , , and loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause.
RESULTS
In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups.
CONCLUSIONS
Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).
Topics: Adult; Humans; Bronchiolitis Obliterans Syndrome; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Methotrexate; Mycophenolic Acid; Neoplasm Recurrence, Local; Tacrolimus; Unrelated Donors; Hematologic Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37342922
DOI: 10.1056/NEJMoa2215943 -
JAMA Jun 2023Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were...
IMPORTANCE
Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome.
OBJECTIVE
To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement.
DESIGN, SETTING, AND PARTICIPANTS
This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity.
EXPOSURE
Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion.
MAIN OUTCOMES AND MEASURES
The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes.
RESULTS
Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%).
CONCLUSIONS AND RELEVANCE
CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.
Topics: Humans; Antigens, CD19; Leukocytes, Mononuclear; Lung Diseases, Interstitial; Mycophenolic Acid; Myositis; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Cyclophosphamide; Immunosuppressive Agents
PubMed: 37367976
DOI: 10.1001/jama.2023.8753 -
Nephrology, Dialysis, Transplantation :... Jan 2024Among the broad spectrum of membranoproliferative glomerulonephritis (MPGN), immunofluorescence distinguishes C3 glomerulopathy (C3G), with predominant C3 deposits, and... (Review)
Review
Among the broad spectrum of membranoproliferative glomerulonephritis (MPGN), immunofluorescence distinguishes C3 glomerulopathy (C3G), with predominant C3 deposits, and immunoglobulin-associated MPGN (Ig-MPGN), with combined C3 and Ig. However, there are several intersections between C3G and Ig-MPGN. Primary C3G and Ig-MPGN share the same prevalence of low serum C3 levels and of abnormalities of the alternative pathway of complement, and patients who present a bioptic pattern of Ig-MPGN at onset may show a C3G pattern in a subsequent biopsy. There is no specific therapy for primary C3G and Ig-MPGN and prognosis is unfavourable. The only recommended indications are inhibitors of the renin-angiotensin system, lipid-lowering agents and other renoprotective agents. The other drugs used currently, such as corticosteroids and mycophenolate mofetil, are often ineffective. The anti-C5 monoclonal antibody eculizumab has been tested in several patients, with mixed results. One reason for the uncertainty is the extremely variable clinical course, most likely reflecting a heterogeneous pathogenesis. An unsupervised clustering analysis that included histologic, biochemical, genetic and clinical data available at onset in patients with primary C3G and Ig-MPGN identified four clusters characterized by specific pathogenic mechanisms. This approach may facilitate accurate diagnosis and development of targeted therapies. Several trials are ongoing with drugs targeting different molecules of the complement cascade, however it is important to consider which component of the cascade may be the most appropriate for each patient. We review the current standards of treatment and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of C3G and Ig-MPGN.
Topics: Humans; Glomerulonephritis, Membranoproliferative; Complement C3; Immunoglobulins; Complement Activation; Fluorescent Antibody Technique
PubMed: 37604793
DOI: 10.1093/ndt/gfad182 -
Life (Basel, Switzerland) Jul 2023Systemic lupus erythematosus (SLE), the prototype of systemic autoimmune diseases is characterized by extreme heterogeneity with a variable clinical course. Renal... (Review)
Review
Systemic lupus erythematosus (SLE), the prototype of systemic autoimmune diseases is characterized by extreme heterogeneity with a variable clinical course. Renal involvement may be observed and affects the outcome. Hydroxychloroquine should be administered to every lupus patient irrespective of organ involvement. Conventional immunosuppressive therapy includes corticosteroids, methotrexate, cyclophosphamide, mycophenolate mofetil, azathioprine, cyclosporine and tacrolimus. However, despite conventional immunosuppressive treatment, flares occur and broad immunosuppression is accompanied by multiple side effects. Flare occurrence, target organ involvement, side effects of broad immunosuppression and increased knowledge of the pathogenetic mechanisms involved in SLE pathogenesis as well as the availability of biologic agents has led to the application of biologic agents in SLE management. Biologic agents targeting various pathogenetic paths have been applied. B cell targeting agents have been used successfully. Belimumab, a B cell targeting agent, has been approved for the treatment of SLE. Rituximab, an anti-CD20 targeting agent is also used in SLE. Anifrolumab, an interferon I receptor-targeting agent has beneficial effects on SLE. In conclusion, biologic treatment is applied in SLE and should be further evaluated with the aim of a good treatment response and a significant improvement in quality of life.
PubMed: 37511872
DOI: 10.3390/life13071496 -
Journal of Ayub Medical College,... 2023A multi-organ granulomatous disease with characteristic lung manifestations, sarcoidosis generally responds well to glucocorticoid therapy but 10% of cases are...
A multi-organ granulomatous disease with characteristic lung manifestations, sarcoidosis generally responds well to glucocorticoid therapy but 10% of cases are refractory necessitating immunosuppressive therapy. A 58-year-old lady presented with a dry cough and progressively worsening shortness of breath for the last 12 months. On investigation, her ESR was raised but cultures, malignancy screen and TB quantiferon were negative. HRCT chest demonstrated multiple pulmonary nodules with hilar lymphadenopathy and CT guided biopsy revealed non-caseating granuloma. She was diagnosed with Pulmonary Sarcoidosis and started on oral steroids with minimal improvement. Azathioprine was added but due to gastric intolerance switched to methotrexate. Her disease however continued to worsen and infliximab was started but she developed a severe allergic reaction. She was then started on mycophenolate mofetil but her chest imaging continued to worsen. After failing prednisone, azathioprine, methotrexate, infliximab and mycophenolate mofetil, the patient was started on rituximab.
Topics: Humans; Female; Middle Aged; Methotrexate; Infliximab; Mycophenolic Acid; Azathioprine; Sarcoidosis; Granuloma
PubMed: 38404097
DOI: No ID Found -
Arthritis Research & Therapy Jul 2023Many clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease... (Review)
Review
Many clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD).Herein, we summarize the results of clinical trials, including patient-reported outcome instruments, for the treatment of patients with ILD associated with systemic sclerosis (SSc/scleroderma), rheumatoid arthritis, and idiopathic inflammatory myositis, the diseases with the most available data. For SSc-ILD, the US Food and Drug Administration approved nintedanib (a tyrosine kinase inhibitor) in 2020 and subcutaneous tocilizumab (an IL-6 receptor monoclonal antibody) in 2021. Rituximab was recently shown to have similar efficacy but better tolerability than intravenous cyclophosphamide (CYC) for CTD-ILD therapy. Scleroderma Lung Study II, conducted in patients with SSc-ILD, showed that oral CYC and mycophenolate mofetil (MMF) were comparable in their effects on lung function, but MMF was better tolerated. The increasing treatment armamentarium for patients with CTD-ILD offers physicians new opportunities to improve patient outcomes.
Topics: Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Connective Tissue Diseases; Cyclophosphamide; Mycophenolic Acid; Scleroderma, Systemic; Scleroderma, Localized; Lung
PubMed: 37422652
DOI: 10.1186/s13075-023-03090-y -
Journal of Ayub Medical College,... 2023We present the case of a 30-year-old woman who presented with 8-month history of intermittent fever, joint pains with morning stiffness, recurrent oral ulcers,...
We present the case of a 30-year-old woman who presented with 8-month history of intermittent fever, joint pains with morning stiffness, recurrent oral ulcers, photosensitivity, weight loss and hair fall. For the last 2 months, she had developed a dry cough with progressive shortening of breath. On examination, a cachexic lady with malar hyperpigmentation, alopecia, pallor, nail dystrophy and erythema over her hands and feet were noted. There were multiple punched-out skin ulcers of variable size over legs, arms and abdomen usually round in shape with well-defined even wound margins and scant serous discharge. Musculoskeletal examination revealed synovitis of both elbows and a few metacarpophalangeal and proximal interphalangeal joints. Chest X-ray and HRCT showed bilateral ground-glass opacification. Anti-Nuclear Antibody (ANA) was positive, 1:320, homogenous nuclear pattern. Anti-Ro antibody was highly positive and serum complement (C3, C4) levels were reduced. She was diagnosed with Lupus Vasculitis and started on steroids, mycophenolate mofetil and hydroxychloroquine.
Topics: Humans; Female; Adult; Mycophenolic Acid; Fever; Arthralgia; Vasculitis
PubMed: 38404096
DOI: 10.55519/JAMC-03-10849 -
Transplant International : Official... 2023Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible...
Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible deceased donor. These French consensus guidelines have been generated by an expert working group, in order to homogenize patient selection, associated treatments and follow-up. This initiative is part of an international effort to analyze properly the benefits and tolerance of this new costly treatment in real-life. Eligible patients must meet the following screening criteria: cPRA ≥ 98%, ≤ 65-year of age, ≥ 3 years on the waiting list, and a low risk of biopsy-related complications. The final decision to use Imlifidase will be based on the two following criteria. First, the results of a virtual crossmatch on recent serum, which shall show a MFI for the immunodominant donor-specific antibodies (DSA) > 6,000 but the value of which does not exceed 5,000 after 1:10 dilution. Second, the post-Imlifidase complement-dependent cytotoxicity crossmatch must be negative. Patients treated with Imlifidase will receive an immunosuppressive regimen based on steroids, rATG, high dose IVIg, rituximab, tacrolimus and mycophenolic acid. Frequent post-transplant testing for DSA and systematic surveillance kidney biopsies are highly recommended to monitor post-transplant DSA rebound and subclinical rejection.
Topics: Adult; Humans; Child, Preschool; Kidney Transplantation; Histocompatibility Testing; HLA Antigens; Graft Rejection; Immunosuppressive Agents; Antibodies; Isoantibodies
PubMed: 37448448
DOI: 10.3389/ti.2023.11244