trimethoprim--sulfamethoxazole-drug-combination and Anti-Neutrophil-Cytoplasmic-Antibody-Associated-Vasculitis

To assess available evidence from randomized controlled trials (RCTs) and observational studies including a control group regarding the role of trimethoprim/sulfametoxazole (TMP/SMX) in reducing the relapse rate in patients with granulomatosis with polyangiitis (GPA) and the risk of infections in patients with ANCA-associated vasculitis (AAV).. MEDLINE, EMBASE, The Cochrane Library databases, Scopus, Web of Science and ClinicalTrials.gov were searched from inception until 15 January 2020 to identify controlled studies assessing the role of TMP/SMX in reducing the rate of relapse in patients with GPA (primary outcome) and the number and/or severity of infections in patients with AAV (secondary outcome). Two reviewers independently selected eligible studies and extracted data. Cumulative risk ratios (RRs) with 95% CI were calculated using a random effect meta-analysis.. Eight studies were selected out of 2907 records. Seven studies (520 patients) (of which two were RCTs) assessed the role of TMP/SMX in the relapse rate in patients with GPA. TMP/SMX was not associated with a reduced risk of relapse (RR = 1.15, 95% CI: 0.51, 2.55; I2 = 78.5%; P < 0.001). Sensitivity analysis according to the dose of TMP/SMX (960 mg twice daily vs three times/week) confirmed the results. One retrospective cohort study (192 patients) was identified demonstrating a significant reduction of severe infections in patients with AAV receiving prophylaxis with TMP/SMX in association with rituximab.. TMP/SMX was not associated with a reduced risk of relapse in patients with GPA. TMP/SMX might be useful in the reduction of infectious complications.. CRD42019118983.

Topics: Anti-Bacterial Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Humans; Secondary Prevention; Trimethoprim, Sulfamethoxazole Drug Combination

In antineutrophil cytoplasmic antibodies-associated vasculitis (AAV), the treatment of choice is either Rituximab or cyclophosphamide in combination with steroids. In less extended forms of AAV, however, less toxic regimens are being used.In the current review, we will focus on the role of one of these less toxic regimens, that is trimethoprim-sulfamethoxazole monotherapy as induction treatment or as maintenance therapy in AAV.. A substantial portion of patients with active granulomatosis with polyangiitis (GPA) limited to the upper airways can be initially controlled with trimethoprim-sulfamethoxazole (2 × 960 mg/day) monotherapy. In patients with initially a complete response, long-term control of the disease seems possible. In addition, trimethoprim-sulfamethoxazole (2 × 960 mg/day) maintenance therapy is an option for patients with GPA that have been proven to be frequent relapsers. The mechanism by which trimethoprim-sulfamethoxazole works in GPA is at present unknown. Suppression of Staphylococcus aureus carriage and/or anti-inflammatory mechanisms has been postulated.. Trimethoprim-sulfamethoxazole may be considered as a safe initial treatment in GPA patients with disease localized to the ear, nose, and throat region. Furthermore, trimethoprim-sulfamethoxazole in a dose of 2 × 960 mg/day may be used to prevent relapses in GPA.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Recurrence; Trimethoprim, Sulfamethoxazole Drug Combination

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are potentially life-threatening disorders.. Even though immunosuppressive therapy improves the prognosis, adverse events, either attributable to persistent disease activity or side effects of treatment remain a challenge. Infectious complications are the leading cause of death in the first year after diagnosis and a major cause of morbidity and mortality thereafter.. Their incidence in clinical trials varies considerably but opportunistic and life-threatening infections, such as Pneumocystis jirovecii pneumonia or systemic cytomegalovirus infections, are frequent and thus predisposing/risk factors need to be defined. Pneumocystis jirovecii pneumonia has been associated with a lymphocyte count below 300/mm(3) . Additionally, besides the aggressiveness of the immunosuppressive regimen administered (especially the cumulative dose of steroids and cyclophosphamide), an elevated serum creatinine or dialysis dependency, older age and pulmonary involvement increase the rate of infectious complications.. We suggest to routinely prescribe trimethoprim-sulfamethoxazole or antimicrobial agents such as pentamidine in case of intolerance or contraindication in the early phase of induction therapy irrespective of the immunosuppressive strategy used and to continue therapy, together with other targeted measures (antiviral, antimycotic or antibiotic) in the presence of risk factors for a prolonged period of time. Finally, there is an urgent need to standardize the reporting of infectious complications in clinical trials to enable comparing the adverse event spectrum of distinct treatment approaches more appropriately.

Topics: Anti-Infective Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibiotic Prophylaxis; Clinical Trials as Topic; Humans; Infection Control; Observational Studies as Topic; Pentamidine; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination

ANCA-associated vasculitides are rare and complex systemic diseases. Collaborative studies in both Europe and the United States of America have been particularly important in the development of randomized clinical trials that have studied the safety of maintenance therapy for these diseases. Although cyclophosphamide continues to be the main drug utilized during induction therapy, its long-term side effects have given rise to the study of other immunosuppressive drugs for the maintenance phase. We herein review these studies with particular attention to combination therapy and the duration of treatment.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Early Diagnosis; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Induction Chemotherapy; Isoxazoles; Leflunomide; Maintenance Chemotherapy; Methotrexate; Randomized Controlled Trials as Topic; Rituximab; Severity of Illness Index; Trimethoprim, Sulfamethoxazole Drug Combination

Severe infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial.. Data on 197 patients recruited into the RAVE trial were analysed. Participants received either rituximab (RTX) or cyclophosphamide (CYC), followed by azathioprine (AZA). Clinical and laboratory data of patients with and without severe infections (≥grade 3, according to the Common Terminology Criteria for Adverse Events version 3.0) were compared. Risk factors for severe infections were investigated using Cox-regression models.. The use of low-dose TMP/SMX is associated with reduced risk of severe infections in patients with AAV treated with either RTX or CYC/AZA. Reduced B cell subpopulations at start of treatment might be a useful correlate of reduced immunocompetence.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Cyclophosphamide; Humans; Remission Induction; Risk Factors; Rituximab; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

To evaluate rituximab (RTX) resistance at 3months (M3) of induction therapy in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV).. Multicentre French retrospective study conducted between 2010 and 2020 including patients with newly diagnosed or relapsing AAV (granulomatosis with polyangiitis or microscopic polyangiitis) having received induction therapy with RTX. Primary endpoint was the presence of RTX resistance at 3months (M3) defined as uncontrolled disease (worsening feature on the BVAS/WG 1month after RTX induction) or disease flare (increase in BVAS/WG of≥1 point before M3).. Out of 121 patients included, we analysed 116 patients. Fourteen patients (12%) had RTX resistance at M3 with no difference in baseline demographics, vasculitis type, ANCA type, disease status or organ involvement. Patients with RTX resistance at M3 had a greater proportion of localized disease (43% vs. 18%, P<0.05) and were less often treated by initial methylprednisolone (MP) pulse (21% vs. 58%, P<0.01). Out of the 14 patients with RTX resistance, seven received additional immunosuppressive therapy. All patients were in remission at 6months. Compared to responders, patients with RTX resistance at M3 were less often treated with prophylactic trimethoprim-sulfamethoxazole (57% vs. 85%, P<0.05). Twenty-four patients died during follow-up, one-third of them from infections and half of them from SARS-CoV-2.. Twelve percent of patients had RTX resistance at M3. These patients more often had localized form of the disease and were less treated by initial MP pulse and by prophylactic trimethoprim-sulfamethoxazole.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; COVID-19; Humans; Induction Chemotherapy; Remission Induction; Retrospective Studies; Rituximab; SARS-CoV-2; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Antibiotic prophylaxis is recommended during ANCA-associated vasculitis (AAV) induction. We aimed to describe the frequency, persistence, and factors associated with trimethoprim-sulfamethoxazole (TMP-SMX) use in an adult population sample with granulomatosis with polyangiitis (GPA) treated with rituximab (RTX).. We identified adults with GPA treated with RTX within the Merative™ Marketscan® Research Databases (2011-2020). TMP-SMX prophylaxis was defined as a [Formula: see text] 28-day prescription dispensed within a month of starting RTX. We estimated TMP-SMX persistence, allowing prescription refill gaps of 30 days. Multivariable logistic regression and Cox proportional hazards regression assessed the factors associated with baseline TMP-SMX use and persistence, respectively. Covariates included age, sex, calendar year, insurance type, immunosuppressant use, hospitalization, and co-morbidities.. Among 1877 RTX-treated GPA patients, the mean age was 50.9, and 54% were female. A minority (n = 426, 23%) received TMP-SMX with a median persistence of 141 (IQR 83-248) days. In multivariable analyses, prophylaxis was associated with prednisone use in the month prior to RTX ([Formula: see text] 20 mg/day vs none, OR 3.96; 95% CI 3.0-5.2; 1-19 mg/day vs none, OR 2.63; 95% CI 1.8-3.8), and methotrexate use (OR 1.48, 95% CI 1.04-2.1), intensive care (OR 1.95; 95% CI 1.4-2.7), and non-intensive care hospitalization (OR 1.56; 95% CI 1.2-2.1) in the 6 months prior to RTX. Female sex (OR 0.63; 95% CI 0.5-0.8) was negatively associated with TMP-SMX use.. TMP-SMX was dispensed to a minority of RTX-treated GPA patients, more often to those on glucocorticoids and with recent hospitalization. Further research is needed to determine the optimal use and duration of TMP-SMX prophylaxis following RTX in AAV.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Retrospective Studies; Rituximab; Trimethoprim, Sulfamethoxazole Drug Combination; United States

This study aimed to explore clinical features of early infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to identify the association between the infection profile of patients with AAV during the first 3 months and 1-year survival.. A total of 415 newly diagnosed patients with AAV in the Department of Nephrology at Shanghai Ruijin Hospital from 2000 to 2018 were included. Four Cox regression models were used to analyse the association based on demographics, comorbidities, laboratory baseline index and therapy parameter. Infection screening was carried out monthly during the first 3 months after diagnosis.. In all, 377 episodes of infection were identified among 220 patients during the first 3 months. The overall survival after 1 year was 73.0%. Respiratory infection (210 episodes/164 persons) accounted for more than half of infections. Infection was independently associated with 1-year mortality (adjusted HR 2.32, 95% CI 1.27 to 4.23, p=0.006) after adjustment. Respiratory infection (adjusted HR 4.36, 95% CI 2.86 to 8.06, p<0.001), Gram-negative bacterial infection (adjusted HR 1.71, 95% CI 1.01 to 2.91, p=0.047) and fungal infection (adjusted HR 1.77, 95% CI 1.07 to 2.94, p=0.026) was identified as a risk factor for 1-year mortality. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis (adjusted HR 0.55, 95% CI 0.31 to 0.97, p=0.040) was protective for 1-year mortality.. Infections, particularly respiratory infections, are a common and important class of complication in patients with AAV and are associated with early mortality. TMP-SMX prophylaxis might be necessary to improve short-term outcome. More consideration of infectious risk and regular infection screening should be given.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; China; Humans; Retrospective Studies; Trimethoprim, Sulfamethoxazole Drug Combination

To identify the role of Staphylococcus aureus (SA) or its intracellular small-colony variant phenotype (SCV) with co-trimoxazole (CTX) or ANCA-associated vasculitis (AAV) activity.. All consecutive AAV patients with granulomatosis with polyangiitis (GPA), eosinophilic GPA or microscopic polyangiitis, followed at the French National Vasculitis Referral Center (09/2012-05/2013), and hospitalized non-AAV controls, exclusively for SA/SCV carriage comparisons, were enrolled. All had bilateral anterior nasal swab cultures. Nasal SA or SCV carriage was determined and associations with relapse(s), BVAS, ANCA-positivity, anti-staphylococcal and immunosuppressant use, were analysed ⩾4 years post-inclusion.. Nasal SA carriage rates did not differ among AAVs (P = 0.53): GPA (24/80; 30%), EGPA (7/28; 25%) and microscopic polyangiitis (3/11; 27.3%); and the rate was less frequent in controls than in GPA patients not taking CTX (P = 0.04). AAV patients taking CTX prophylaxis had less nasal SA carriage (8.7% vs 36.2%; P = 0.02). Nasal SA carriage or CTX use did not modify relapse rates, BVAS or ANCA-positivity at inclusion or during follow-up. Nasal SCV carriage, found in 15/207 (7.2%) patients, was similar for GPA (10/24; 41.7%), microscopic polyangiitis (2/7; 28.6%) and eosinophilic GPA (2/3; 66.7%), but higher (P = 0.02) than controls (1/14; 7.1%). SCV carriage by AAV groups did not modify relapse rates or ANCA positivity at inclusion or during follow-up; a trend towards higher BVAS was observed only for anti-PR3 ANCA patients.. Nasal SA or SCV carriage was comparable among AAVs but more frequent than in controls. Nasal SA or SCV carriage and CTX use did not modify AAV relapse rates.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibiotic Prophylaxis; Churg-Strauss Syndrome; Female; France; Granulomatosis with Polyangiitis; Humans; Male; Microscopic Polyangiitis; Middle Aged; Nasal Cavity; Phenotype; Prospective Studies; Recurrence; Secondary Prevention; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Agammaglobulinemia; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antirheumatic Agents; Churg-Strauss Syndrome; Delphi Technique; Duration of Therapy; Granulomatosis with Polyangiitis; Humans; Immunocompromised Host; Influenza Vaccines; Influenza, Human; Maintenance Chemotherapy; Microscopic Polyangiitis; Neutropenia; Pneumococcal Infections; Pneumococcal Vaccines; Pneumonia, Pneumocystis; Practice Guidelines as Topic; Recurrence; Rituximab; Trimethoprim, Sulfamethoxazole Drug Combination; United Kingdom

Topics: Anti-Infective Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cytoplasm; Humans; Infections; Rituximab; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cytoplasm; Humans; Hydroxychloroquine; Infections; Rituximab; Trimethoprim, Sulfamethoxazole Drug Combination

We aimed to assess risk factors for the development of severe infection in patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) receiving rituximab.. 192 patients with AAV were identified. Univariate and multivariate analyses were performed to identify risk factors for severe infection following rituximab. Severe infections were classified as grade ≥3 as proposed by the Common Terminology Criteria for Adverse Events V.4.0.. 95 severe infections were recorded in 49 (25.52%) patients, corresponding to an event rate of 26.06 per 100 person-years. The prophylactic use of trimethoprim-sulfamethoxazole was associated with a lower frequency of severe infections (HR 0.30, 95% CI 0.13 to 0.69), while older age (HR 1.03, 95% CI 1.01 to 1.05), endobronchial involvement (HR 2.21, 95% CI 1.14 to 4.26), presence of chronic obstructive pulmonary disease (HR 6.30, 95% CI 1.08 to 36.75) and previous alemtuzumab use (HR 3.97, 95% CI 1.50 to 10.54) increased the risk. When analysis was restricted to respiratory tract infections (66.3% of all infections), endobronchial involvement (HR 4.27, 95% CI 1.81 to 10.06), severe bronchiectasis (HR 6.14, 95% CI 1.18 to 31.91), higher neutrophil count (HR 1.19, 95% CI 1.06 to 1.33) and major relapse (HR 3.07, 95% CI 1.30 to 7.23) as indication for rituximab use conferred a higher risk, while refractory disease (HR 0.25, 95% CI 0.07 to 0.90) as indication had a lower frequency of severe infections.. We found severe infections in one quarter of patients with AAV receiving rituximab. Trimethoprim-sulfamethoxazole prophylaxis reduced the risk, while especially bronchiectasis and endobronchial involvement are risk factors for severe respiratory infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibiotic Prophylaxis; Female; Humans; Immunologic Factors; Male; Middle Aged; Multivariate Analysis; Respiratory Tract Infections; Risk Factors; Rituximab; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

Cutaneous leukocytoclastic vasculitis (LCV) can occur as skin-limited disease or as part a systemic vasculitis. Appropriate workup includes the evaluation of antineutrophil cytoplasmic antibodies (ANCAs), with a positive titer raising concern for the associated primary vasculitides including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), or eosinophilic granulomatosis with polyangiitis (EGPA). In the absence of systemic findings, however, a drug etiology must also be considered. Tumor necrosis factor (TNF) inhibitors, propylthiouracil, levamisole-adulterated cocaine, hydralazine, and minocycline have been previously documented to induce ANCA-positive vasculitis (APV), which may present with conspicuously high ANCA titers. Herein we report trimethoprim-sulfamethoxazole as another culprit in drug-induced APV. Our case reinforces the need to consider drug etiology for APV and cautions against interpreting positive ANCAs as equivalent to evidence of systemic disease.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Trimethoprim, Sulfamethoxazole Drug Combination

A 76-year-old man was admitted to our hospital because of severe anemia. Routine screening revealed a sigmoid adenocarcinoma, and he underwent sigmoidectomy. Post-operatively, he developed rapidly progressive glomerulonephritis. He was positive for myeloperoxidase anti-neutrophil cytoplasmic antibody. A renal biopsy revealed idiopathic crescentic glomerulonephritis of the pauci-immune type. He was treated with methylprednisolone semi-pulse therapy with clinical improvement. After the steroid pulse therapy, he was given oral prednisolone, 40 mg per day, and oral trimethoprim (TMP), 160 mg, and sulfamethoxazole (SMX), 800 mg twice weekly for chemoprophylaxis against pneumocystis pneumonia. One month after the initiation of TMP/SMX, he developed hyperkalemia and hyponatremia. His transtubular K gradient was low, and urinary potassium excretion was decreased. On the other hand, plasma renin activity and plasma aldosterone concentrations were within normal limits. These results suggested that TMP acted similarly to a potassium-sparing diuretic amiloride and reduced renal potassium excretion. Administration of calcium polystyrene sulfonate resulted in correction of the hyperkalemia without discontinuation of TMP/SMX. We emphasize that patients with impaired renal function are at the significant risk of developing trimethoprim-induced hyperkalemia even with chemoprophylaxis.

Topics: Adenocarcinoma; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibiotic Prophylaxis; Glomerulonephritis; Humans; Hyperkalemia; Immunocompromised Host; Male; Pneumonia, Pneumococcal; Postoperative Complications; Sigmoid Neoplasms; Trimethoprim, Sulfamethoxazole Drug Combination