Acute interstitial nephritis and PR3-ANCA following reintroduction of pembrolizumab: a case report.

Renal toxicity from immune checkpoint inhibitors (ICIs) is an increasingly recognized cause of acute kidney injury among patients with cancer. ICI-associated acute kidney injuries typically present as acute interstitial nephritis and the timing of onset is highly variable. Herein, we present a case of a patient with relapsed metastatic melanoma previously treated with pembrolizumab who developed grade 3 immune-related renal toxicity after reintroduction of the same ICI, secondary to acute interstitial nephritis with accompanying high PR3-antineutrophil cytoplasmic antibody titer. The patient improved after steroid treatment and discontinuation of pembrolizumab. This case highlights the importance of not excluding ICI-related nephrotoxicity as a possible cause of renal failure, including in those who previously tolerated ICI treatment, since it is a treatable entity.

Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited.

BACKGROUND AND OBJECTIVES: Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients. METHODS: Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase 3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used. RESULTS: Our pharmacokinetic and pharmacokinetic-pharmacodynamic (PK-PD) models satisfactorily described both concentration-time and concentration-effect relationship data. The mean (inter-individual standard deviation) estimated non-specific clearance was 0.15 L/day (0.30%) and the target-mediated elimination rate constant was 2.4 × 10-5 nmol/day. The elimination half-lives for MPO-ANCA and PR3-ANCA were 24 and 18 days, respectively. CONCLUSIONS: A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab.

Paquimeningitis hipertrófica en vasculitis anca positivo: reporte de caso y revisión de la literatura / Hypertrophic pachymeningitis in positive ANCA vasculitis: case report and literature review

La paquimeningitis hipertrófica (PH), es una manifestación poco frecuente de la vasculitis asociada a anticuerpos anti-citoplasma de neutrófilo (ANCA). La literatura describe compromiso de sistema nervioso central (SNC) en 2-8% de los casos en pacientes con vasculitis pauciinmune. Se presenta el caso de un paciente con antecedente de vasculitis anti-mieloperoxidasa (MPO) con un mes de evolución de cefalea hemicraneana izquierda. La resonancia magnética cerebral contrastada evidencia marcado engrosamiento y realce meníngeo dural en el hemicráneo izquierdo, predominante en el tentorio y la fosa posterior. Se descartaron causas infecciosas por lo que se llegó a la conclusión de compromiso meníngeo asociado a vasculitis. Se inició manejo inmunosupresor con mejoría del cuadro clínico. La rápida identificación y manejo de esta entidad puede cambiar su pronóstico sombrío. Se realizó una revisión de la literatura para brindar una herramienta para la toma de decisiones para los médicos que se enfrentan a esta entidad.

Hypertrophic pachymeningitis (PH) is a rare manifestation of vasculitis associated with anti-neutrophil cytoplasm antibodies (ANCA). The literature describes central nervous system (CNS) involvement in 2-8% of cases in patients with pauciimmune vasculitis. We present the case of a patient with a history of anti-Myeloperoxidase (MPO) vasculitis with a 1-month history of left-sided headache. Contrast brain magnetic resonance was performed with evidence of marked thickening and dural meningeal enhancement in the left hemicranium, predominantly in the region of the tentorium and posterior fossa. Infectious causes were ruled out and the meningeal compromise associated with vasculitis was concluded. Immunosuppressive management was started with improvement of the clinical picture. Rapid identification and management of this entity can change its bleak outlook. A systematic review of the literature was carried out in order to provide a decision-making tool for physicians facing this entity.

Morphologically proved ANCA positive Loeffler's pancarditis: medical and surgical treatment.

Loeffler's endocarditis remains is a very rare disease, develops due to eosinophilic inflammation predominantly of the endocardium with an outcome in fibrosis and massive thrombus formation and. He is generally characterized by an unfavorable prognosis. Clinical case of a 42-year-old patient with Loeffler endocarditis is presented. The development of the disease was preceded by a polyvalent allergy, mild dry eye syndrome and pansinusitis with a single eosinophilia of blood up to 16%. The reason for the hospitalization was the appearance of biventricular heart failure. During the previous year, the level of blood eosinophils remained normal, a threefold increase in the level of eosinophilic cationic protein was observed once. A 20-fold increase in the pANCA level, a 2.5-fold increase in the level of antibodies to DNA, an antibody to the nuclei of cardiomyocytes 1:160 were detected. The diagnosis was made on the basis of electrocardiography data (low QRS voltage, atrial hypertrophy), echocardiography, multispiral computed tomography and magnetic resonance imaging of the heart (thickening and delayed contrasting of the endocardium, massive thrombosis of the left ventricular apex with obliteration of its cavity, encapsulated fluid in the pericardium with compression of the right ventricle). Systolic dysfunction, severe signs of restriction and arrhythmias were absent. Trombectomy, tricuspid valve plasty, pericardial resection, suturing of an open oval window were performed. Signs of active inflammation with single eosinophils, vasculitis, perimuscular sclerosis, endocardial sclerosis were detected in morphological and immunohistochemical studies of endo-, myo-, pericardium. Viral genome was not found. The therapy with methylprednisolone 24 mg/day, azathioprine 75 mg/day was started. Six months after the operation, the symptoms of heart failure are completely absent, the thrombosis did not recur.

c-ANCA vasculitis after initiation of denosumab.

Denosumab is a fully human antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), and it is administered every 6 months in women with postmenopausal osteoporosis (PMO) at high risk for fracture. Adverse effects of denosumab include musculoskeletal pain, hypercholesterolaemia, symptomatic hypocalcaemia, osteonecrosis of the jaw and cutaneous events such as angioedema, cellulitis and pustular dermatitis. While the possibility of vasculitis was mentioned in the product Monograph as well as in the WHO Newsletter, this is the first case, to our knowledge, of cytoplasmic-ANCA (c-ANCA) associated vasculitis officially published in the literature. 1 2 The pathogenic mechanisms behind drug-induced vasculitis remain to be defined and appear to be multifactorial. Once suspicion for drug-induced vasculitis arises, the offending agent should be discontinued and immunosuppressive therapy should be initiated according to the severity of organ involvement to inhibit progression to severe, irreversible disease. As new medications continue to be developed, the number of agents causing drug-induced vasculitis is expected to increase.

Successful Management of Lupus Nephritis with High Titers of Myeloperoxidase Anti-Neutrophil Cytoplasmic Antibodies Using Tacrolimus.

A 63-year-old Japanese woman with a 30-year history of systemic lupus erythematosus developed macrohematuria and massive proteinuria after seroconversion of myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy indicated focal proliferative lupus nephritis (class III A/C) with a fibrous crescent formation. Methylprednisolone pulse therapy (500 mg, 3 successive days) was administered because of progressive proteinuria. Steroid therapy did not suppress the progressive proteinuria; therefore, tacrolimus was added as an alternative immunosuppressive therapy, resulting in the improvement of proteinuria and renal impairment. This case report suggests that MPO-ANCA might play a pathogenic role in the exacerbation of immune-complex-type lupus nephritis.

Efficacy and safety of rituximab in rheumatic diseases.

B-cell depleting therapy is now in clinical use for more than 10 years in rheumatology. In 2001, a first report was published on five rheumatoid arthritis patients responding to the chimeric anti-CD20 antibody rituximab. Since then, numerous clinical trials, prospective and retrospective studies, registry data as well as case reports on the use of rituximab in autoimmune rheumatic diseases have been published. This review gives a short overview on clinical data of rituximab in rheumatic diseases currently available.

Segmental testicular infarction due to minocycline-induced antineutrophil cytoplasmic antibody--positive vasculitis.

Segmental testicular infarction is an uncommon clinical entity marked by acute scrotal pain and swelling. Classically, these appear as wedge-shaped, avascular, hypoechoic lesions on a testicular ultrasound. We present a unique case of testicular infarct caused by an antineutrophil cytoplasmic antibody-positive vasculitis secondary to the use of the antibiotic minocycline. The patient's symptoms resolved with cessation of minocycline. We suggest that patients who present with otherwise unexplained testicular infarction undergo a careful review of medications to uncover a potential cause.

Recent advances to achieve remission induction in antineutrophil cytoplasmic antibody-associated vasculitis.

PURPOSE OF REVIEW: Significant advances in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis have been made in the past 10 years. This review aims to detail advances in treatment aimed at induction of remission. RECENT FINDINGS: Cyclophosphamide-based regimes remain the standard of care, at least in generalized disease. Safer therapeutic regimes with reduced cumulative dose of cyclophosphamide have been developed such as the use of pulsed cyclophosphamide. Preliminary data are available, suggesting rituximab may be an alternative to cyclophosphamide, but additional safety data are required. Evidence suggests that plasma exchange should be added to those with more severe disease and it is acceptable to use methotrexate as an induction agent for those with limited or early systemic disease. Using current regimens, remission is achieved in over 90% of patients, but toxicity remains an important issue. Attention should be paid to reducing treatment toxicity. SUMMARY: Findings of recent clinical trials should change clinical practice and improve outcome of patients with antineutrophil cytoplasmic antibody-associated vasculitis.

Hypertrophic pachymeningitis with MPO-ANCA-positive vasculitis.

A 75-year-old man presented with headache, right facial palsy, and left hemiparesis. Because of elevated myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) titers and findings from magnetic resonance imaging (MRI) which were compatible with hypertrophic pachymeningitis (HP), he was diagnosed with MPO-ANCA-positive HP. He was treated with the combination therapy of steroid and cyclophosphamide (CY), leading to good prognosis. We present a case of HP associated with MPO-ANCA-positive vasculitis and emphasize the importance of MPO-ANCA tests as a predictable factor for relapse of the disease in order to start earlier treatment for the disease.

Effect of rituximab on refractory Wegener granulomatosis with predominant granulomatous disease.

Wegener granulomatosis is an autoimmune disorder with a double spectrum. Vasculitic manifestations are at one end of it, whereas granulomatous ones are at the other. Rituximab (RTX) is a chimeric monoclonal antibody that has been successfully used in this condition. However, the granulomatous forms have been reported to show a tendency to be less responsive to RTX than the vasculitic disease. We present 4 cases of predominantly Wegener granulomatosis that responded positively to RTX.

Dual ANCA positivity in subacute bacterial endocarditis.

Nine cases of subacute bacterial endocarditis (SBE) associated with anti-PR3 ANCA have been described in the literature to date. We describe 2 cases of SBE associated with dual ANCA positivity (anti-PR3 and anti-MPO ANCA.) To our knowledge, these are the first such reported cases. One case was associated with cutaneous vasculitis, and the second with predisposing factors for SBE. ANCA titers resolved or decreased in both during initial corticosteroid therapy for suspected vasculitis. Follow-up of these patients revealed no evidence of the common ANCA associations such as Wegener granulomatosis. Rheumatologists, if aware of ANCA association with SBE, can avoid inappropriate immunosuppressive treatments.

Challenges in the management of microscopic polyangiitis: past, present and future.

PURPOSE OF REVIEW: Microscopic polyangiitis is defined within the context of primary systemic vasculitis. The presentation and management of renal involvement in microscopic polyangiitis is discussed, with emphasis on prognosis and outcomes. Potential roles of newer therapies are reviewed. RECENT FINDINGS: The histological features of kidney disease in microscopic polyangiitis have been associated with clinical presentation and renal outcome. The predictive value of antineutrophil cytoplasm antibody positivity after induction therapy has been highlighted. Plasma exchange improves renal recovery rates in severe presentations in a randomized trial. Initial results with rituximab have indicated that the B cell is an important therapeutic target in vasculitis and that B-cell depletion has the potential to replace immune suppressive treatment in the future. SUMMARY: Microscopic polyangiitis is a subgroup of primary systemic vasculitis, but diagnostic problems remain with antineutrophil cytoplasm antibody-negative cases and in those without kidney disease. Plasma exchange has a confirmed place in therapy. The poor outcomes of many patients indicate safer, more effective therapies are required. Improved biomarkers are needed to assist in drug selection, monitoring and prognosis.

Difficult decisions in the intensive care unit: an illustrative case.

Difficult clinical decision-making is a common experience in intensive care units. There is often considerable pressure on time and decisions may have to be made in a stressful environment. Patients in the intensive care unit not infrequently present with extreme or rare manifestations of a disease process. Clinical evidence to guide management of such patients may be incomplete, non-existent, or its relevance to the problem at hand may be questionable. In this context, formal decision-making analytical tools are often impractical. Unconscious cognitive biases have been shown to play an important role in medical decision-making, particularly in these settings. While mostly these contribute to doctors making appropriate and timely decisions, occasionally they lead to errors. Despite 30 years of research into models of clinical reasoning, most doctors are unaware of how biases affect their thinking and are unfamiliar with techniques of detecting and neutralising bias in clinical practice. We present the case of a patient with Wegener's granulomatosis, which highlights many of the difficulties outlined above. We review the clinical evidence for our decisions at each stage and explain the rationale for our choices, highlighting the many situations for which high quality evidence was lacking. Examples of cognitive bias are identified and techniques of metacognition (thinking about thinking) that can be useful in limiting the effects of bias on complex decision-making are reviewed. The intensivist's evaluation of management alternatives has an important role in steering medical management towards optimal patient outcomes.

[Vasculitis with renal involvement and antineutrophil cytoplasmic antibodies (ANCA) in a child receiving benzylthiouracil]. / Vascularite avec atteinte rénale et anticorps anticytoplasme des polynucléaires neutrophiles (ANCA) après prise de benzylthio-uracile chez l'enfant.

Vasculitis associated to antineutrophil cytoplasmic antibodies (ANCA) is a rare complication of therapy with antithyroid medication. They were mainly described in patients treated with propylthiouracil (PTU), carbimazole, methimazole and rarely by benzylthiouracil (Basden). We report a case of 12-years-old girl treated by benzylthiouracil for Grave's disease who developed after 2 years vasculitis associated with cutaneous involvement (generalized ulcer necrotic purpura) and glomerulonephritis with proteinuria of 24 hours at 26 mg/kg/day, microscopic hematuria and renal failure with creatinemia level at 135 micromol/l. The ANCA type antiMPO (myeloperoxidase) was positive. The histology study of the renal needle biopsy was in favour with focal necrotizing glomerulonephritisand crescents with different evolutive stages. The discontinuation of benzylthiouracil and the treatment by the corticoids involved a disappearance of cutaneous lesions, a negative result of proteinuria, a normalization of the renal function (creatinemia=84 micromol/l) and a disappearance of hematuria and ANCA. These results permitted to announce hypothesis that benzylthiouracil was implicated in development of vasculitis associated to ANCA.

CD8+ T lymphocytes infiltrate predominantly in the inflammatory foci of MPO-ANCA-positive thoracic hypertrophic pachymeningitis in a patient with HLA-A24.

Hypertrophic pachymeningitis (HP) is extremely rare and an inflammatory process that thickens the dura mater. A 59-year-old Japanese woman developed backache, became paraplegic, and magnetic resonance imaging revealed diffuse thickening of the thoracic dura mater encompassing the spinal cord. Although a test for myeloperoxidase antineutrophil cytoplasmic autoantibody (MPO-ANCA) was shown to be positive, vasculitis was not found and CD8(+) T lymphocytes that predominated in the inflammatory foci. Both interleukin (IL)-2 and IL-6 were markedly elevated in not only sera but also cerebrospinal fluids, very much higher in the latter. Human leukocyte antigen (HLA) typing revealed A24 positivity, suggesting this molecule was interacting with CD8(+) T lymphocytes. It was suggested that immunological disharmony and autoimmunity would play a pivotal role in the development of HP under genetic background of HLA-A24, and HP would be one feature of multiple organ involvement in ANCA-associated diseases.

Remission in antineutrophil cytoplasmic antibody-associated systemic vasculitis.

The definition of remission in patients with systemic vasculitis must be distinguished from the term "cure," which implies that patients are well and not requiring ongoing therapy. Remission should be defined using a standardised approach to measuring clinical disease activity, and the definition should be qualified by the duration of the remission and the type of maintenance therapy required to sustain remission. Remission is an important goal of management in the systemic vasculitides and is achievable in most patients. Maintenance of remission is a more difficult target, and evidence from studies of patients with antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis indicates that durable, lasting remission is unlikely to occur. Despite good disease control, damage or scarring from disease or its treatment is a common finding and is a separate outcome from remission. Future studies of vasculitis therapies should address the concept of rapid and sustained disease control, so that patients spend most of their time in a state of good health, with minimal damage.