Antineutrophil cytoplasmic antibody-associated vasculitis, abbreviated as AAV, is a systemic autoimmune disease characterized by necrotizing inflammation of small blood vessels. When it strikes both the lungs and the kidneys, clinicians call it pulmonary-renal syndrome, and it ranks among the most lethal presentations of any autoimmune disease. Patients typically develop rapidly progressive glomerulonephritis, in which the kidney’s filtering units are destroyed within days or weeks, alongside pulmonary infiltrates or diffuse alveolar hemorrhage that can suffocate the patient from within. Without aggressive immunosuppressive treatment, mortality is high and kidney failure is often irreversible.

The patient in this case had been in good health until early 2023, with a medical history notable only for kidney stones. In January 2023, routine laboratory tests revealed persistent leukocytosis, an elevated white blood cell count. Over the following months he developed abdominal pain, muscle and joint aches, low-grade fever, fatigue, and swelling of the lower limbs. Multiple courses of empirical antibiotics were administered without any improvement, a pattern that should raise suspicion of a non-infectious cause. His condition then deteriorated dramatically: urine output fell to oliguria and progressed to complete anuria, accompanied by laboratory evidence of severe systemic inflammation.

On admission to the Department of Nephrology at St. George University Hospital in Plovdiv in May 2023, the man was in poor general condition, with arterial hypertension, peripheral edema, pallor, pulmonary congestion, and clinical signs of fluid overload. Laboratory investigations revealed extreme leukocytosis reaching 41 × 10⁹ per liter, thrombocytosis up to 850 × 10⁹ per liter, markedly elevated inflammatory markers, severe acute kidney injury, electrolyte disturbances, and hypoalbuminemia. Serum creatinine, a key marker of kidney failure, reached 700 µmol/L, while potassium climbed to 6.6 mmol/L, a level that threatens fatal cardiac arrhythmia.

Immunological testing provided the diagnostic turning point. The patient tested positive for proteinase 3-ANCA with a cytoplasmic staining pattern, the immunological signature of this form of vasculitis. Critically, antibodies against the glomerular basement membrane were negative, ruling out Goodpasture’s disease, and microbiological cultures showed no infection. Computed tomography of the chest and abdomen revealed bilateral pulmonary infiltrates, pleural and pericardial effusions, pleural-based pulmonary lesions, and enlarged paraaortic lymph nodes, findings that initially kept both severe infection and malignancy in the differential diagnosis.

A percutaneous kidney biopsy settled the question. Light microscopy showed pauci-immune necrotizing crescentic glomerulonephritis, a pattern in which inflammatory cells form crescent-shaped crescents around the glomeruli while immunofluorescence shows little or no immune complex deposition. This histopathological picture is consistent with PR3-ANCA-associated rapidly progressive glomerulonephritis and, importantly, indicated advanced active disease with an unfavorable prognosis for renal recovery. The extent of crescent formation meant that even with perfect treatment, the kidneys were unlikely to regain function.

Treatment began with the standard induction regimen: high-dose corticosteroids and cyclophosphamide, an alkylating chemotherapy agent that has anchored vasculitis therapy for decades. The patient also received hemodialysis, broad-spectrum antimicrobials including meropenem, vancomycin, and metronidazole, thromboembolic prophylaxis with enoxaparin, and human albumin to correct low blood protein levels. Despite this intensive combination, renal recovery was not achieved, and concerns grew about cumulative cyclophosphamide toxicity, which limits prolonged use particularly in critically ill patients already at high risk of infection.

A multidisciplinary team therefore made the decision to escalate to rituximab, an anti-CD20 monoclonal antibody marketed as MabThera. The pharmaceutical rationale was compelling on several fronts. Rituximab works by selectively depleting CD20-positive B lymphocytes, the cells responsible for producing the ANCA antibodies that drive the inflammatory attack. It has demonstrated efficacy comparable to cyclophosphamide for remission induction, with particular effectiveness in PR3-ANCA-positive disease. Crucially for this dialysis-dependent patient, rituximab is not significantly eliminated through the kidneys and is not effectively removed by hemodialysis, so no dose adjustment was necessary. Before initiating the biologic, the team screened for hepatitis B, hepatitis C, and HIV because of the risk of viral reactivation under immunosuppression.

The outcome demonstrated both the power and the limits of modern therapy. Following rituximab administration, systemic inflammatory activity stabilized and the pulmonary involvement regressed, with no new manifestations outside the kidneys during follow-up. However, renal recovery never occurred, and the patient remained chronically dependent on dialysis, a consequence the authors attribute to the advanced crescentic glomerular injury and the delayed diagnosis. The case underscores a sobering reality: controlling the immune attack cannot always reverse damage already done to organs destroyed before treatment began.

Beyond the individual outcome, the report carries broader lessons for the management of severe vasculitis. Delayed diagnosis and high inflammatory burden are associated with irreversible renal damage and increased mortality, making early recognition of ANCA-associated disease essential when patients present with unexplained kidney failure and lung infiltrates. The authors emphasize that careful pharmaceutical monitoring, including complete blood counts, inflammatory markers, electrolytes, immunoglobulin levels to detect hypogammaglobulinemia, and vigilant surveillance for opportunistic infections, remains essential during biologic immunosuppressive therapy. The successful coordination among nephrologists, clinical pharmacists, pathologists, and intensive care specialists in this case illustrates that multidisciplinary care is not an administrative nicety but a determinant of survival in these complex, rapidly evolving diseases.

Subject of Research: Rituximab therapy for severe PR3-ANCA-associated pulmonary-renal syndrome

Article Title: Rituximab therapy in severe PR3 – ANCA pulmonary–renal syndrome: A clinical and pharmaceutical case report

Article References: Nikolov, D., Nikolov, G., Kitova, L., Kitov, S., Kitova, M.-F., & Mihaylova, A. A. (2026). Rituximab therapy in severe PR3-ANCA pulmonary–renal syndrome: A clinical and pharmaceutical case report. Pharmacia, 73, Article e201634. https://doi.org/10.3897/pharmacia.73.e201634

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e201634

Keywords: rituximab, ANCA-associated vasculitis, pulmonary-renal syndrome, PR3-ANCA, glomerulonephritis, case report, autoimmune disease, kidney failure, hemodialysis, immunosuppression, B-cell depletion, clinical pharmacology

COPA syndrome is caused by mutations in the COPA gene, which encodes the alpha subunit of the coatomer protein complex, a cellular machine responsible for shuttling proteins between the endoplasmic reticulum and the Golgi apparatus. When this trafficking system breaks down, proteins accumulate abnormally within cells, triggering cellular stress and activating the type I interferon pathway, a central alarm system of innate immunity. The result is profound immune dysregulation characterized by the production of autoantibodies and chronic inflammation that primarily targets the lungs, kidneys and joints. The condition is usually inherited in an autosomal dominant pattern, although sporadic cases without any family history occur, and the classic clinical triad comprises interstitial lung disease or diffuse alveolar hemorrhage, arthritis and kidney disease.

The patient at the center of the report first fell ill at the age of 27, when he developed flu-like symptoms, coughing up blood and acute respiratory failure severe enough to require orotracheal intubation and eighteen days of mechanical ventilation. Chest computed tomography at that time revealed diffuse alveolar damage and a nonspecific interstitial pneumonia pattern. Within the same year he began showing signs of renal dysfunction, and a year later he suffered a second episode of acute respiratory failure. Given the striking combination of lung bleeding and kidney injury, his physicians initially suspected a pulmonary–renal syndrome such as ANCA-associated vasculitis or Goodpasture syndrome, and in 2008 he was started on an intensive course of twelve cycles of the immunosuppressant cyclophosphamide.

That treatment achieved partial stabilization, but it could not halt the underlying disease. Serial chest CT scans over the following years documented progressive fibrotic damage to the lungs, including upper lobe–predominant honeycombing, increasing reticulation, traction bronchiectasis and persistent ground-glass opacities. By 2022, high-resolution imaging showed established fibrotic remodeling alongside findings suggesting active inflammatory lung injury, a coexistence of chronic scarring and recurrent acute damage that is characteristic of the heterogeneous pulmonary manifestations of COPA syndrome. A transbronchial biopsy yielded inadequate tissue, so the surgical team proceeded to an open lung biopsy. The histopathology proved remarkably rich: prominent lymphoid follicles consistent with follicular bronchiolitis, a non-fibrotic nonspecific interstitial pneumonia pattern with marked interstitial edema, patches of organizing pneumonia containing intra-alveolar fibrin in an acute fibrinous and organizing pneumonia pattern, fibrin thrombi within airspaces, and evidence of both recent and remote alveolar hemorrhage in the form of hemosiderin-laden macrophages.

The kidneys told a parallel story. A renal biopsy performed in November 2008 demonstrated focal proliferative and necrotizing glomerulonephritis with early crescent formation in six of nine glomeruli examined, confirming active immune-mediated renal injury. Immunofluorescence showed no linear deposition of immunoglobulin along the glomerular basement membrane, which definitively excluded Goodpasture syndrome. Serologic testing during reevaluation between 2021 and 2022 revealed a positive antinuclear antibody test at a titer of 1:320 in a homogeneous pattern and a positive p-ANCA at 1:80, but antibodies directed against myeloperoxidase, proteinase 3, double-stranded DNA, Smith, ribonucleoprotein, Ro/SSA and La/SSB were all negative. Kidney function was impaired, with a creatinine clearance of 60 mL per minute and 24-hour proteinuria of 907.5 mg. The atypical ANCA positivity, the authors note, reflects the immune dysregulation inherent to COPA syndrome rather than primary ANCA-associated vasculitis, a distinction with major consequences for classification and treatment.

The definitive answer arrived only in January 2024, when next-generation sequencing identified a heterozygous COPA variant, NM_004371.4:c.698G>A (p.Arg233His), classified as likely pathogenic under American College of Medical Genetics criteria. This variant had been reported previously in individuals with COPA syndrome and is associated with pulmonary and autoimmune manifestations, and its identification finally unified the patient’s pulmonary hemorrhage, crescentic glomerulonephritis and arthralgia under a single genetic diagnosis. Notably, the patient had denied any family history of autoimmune, interstitial lung or renal disease, and genetic testing of relatives was unavailable, underscoring how sporadic presentations can escape suspicion for years. Pulmonary function testing in 2022 revealed a mixed moderate obstructive and restrictive ventilatory defect, with a forced vital capacity of 53 percent predicted, a forced expiratory volume in one second of 44 percent predicted and a markedly reduced diffusing capacity for carbon monoxide at 42 percent predicted. A six-minute walk test showed oxygen saturation falling from 96 percent to 85 percent after only 285 meters.

Once the diagnosis was confirmed, the nephrology team initiated maintenance immunosuppression with methotrexate 10 mg weekly and prednisone 10 mg daily, and the patient remained clinically stable and asymptomatic for roughly a year. The course then deteriorated for reasons that were tragically behavioral as much as biological. The patient self-adjusted his medications, discontinued methotrexate without medical advice because he attributed his symptoms to a viral infection, and stopped attending scheduled follow-up visits. After approximately a year without immunosuppressive therapy, he returned with worsening renal function and significant proteinuria while his lung disease remained stable. Suspecting immune-mediated renal relapse, clinicians began pulse cyclophosphamide at 1 g daily for three consecutive days together with pulse methylprednisolone at the same dose and schedule, with no documented neutropenia during treatment.

Shortly after that single cycle, the patient developed acute diverticulitis complicated by sepsis from a perforated diverticulum, an event for which he had no prior history of diverticular disease. He underwent an emergency Hartmann’s procedure with end colostomy for surgical source control, but despite emergency abdominal surgery and prolonged broad-spectrum antibiotics, he progressed to septic shock and multiorgan failure and died. The case authors emphasize that severe infection during potent immunosuppression is among the principal causes of mortality reported in COPA syndrome, alongside progressive respiratory failure and end-stage kidney disease, and that patients receiving cyclophosphamide and similar agents require particularly vigilant multidisciplinary monitoring.

Beyond its clinical drama, the report carries broader lessons for the field. Because COPA syndrome is rare and phenotypically variable, diagnostic delay is common, especially when adult presentations overlap with far more prevalent autoimmune and interstitial lung diseases. The authors argue that the diagnosis should be suspected in patients with diffuse alveolar hemorrhage, unexplained pulmonary–renal syndromes, follicular bronchiolitis or interstitial lung disease beginning in childhood or early adulthood, particularly when autoantibodies are positive without a definitive connective tissue disease diagnosis. Genetic testing, they contend, should be pursued whenever diagnostic uncertainty persists despite multidisciplinary evaluation. On the therapeutic horizon, Janus kinase inhibitors such as baricitinib and ruxolitinib, which target the type I interferon pathway at the root of the disease, have shown promise in case reports and small studies and may prove especially valuable for severe or refractory disease. The authors call for multicenter studies and international registries to standardize treatment strategies and define the natural history of the condition, and they conclude that early recognition, sustained treatment adherence and careful monitoring during immunosuppressive therapy are essential to prevent relapse and fatal complications in this rare but devastating disorder.

Subject of Research: COPA syndrome, a rare autosomal dominant genetic autoimmune disorder affecting the lungs, kidneys and joints

Article Title: A Rare Case of COPA Syndrome: Multisystem Relapse and Fatal Septic Complication

Article References: Castro Velasco Fernandes, F., Torres, P. P. T. E. S., de Paula Silveira‐Lacerda, E., Rabahi, M., Velasco Magalhaes Fernandes, L., Lopes, L. R., Moreira, M. A. R., & Rabahi, M. F. (2026). A Rare Case of COPA Syndrome: Multisystem Relapse and Fatal Septic Complication. Respirology Case Reports, 14(9), Article e70742. https://doi.org/10.1002/rcr2.70742

Image Credits: AI Generated

DOI: 10.1002/rcr2.70742

Keywords: COPA syndrome, genetic autoimmune disease, interstitial lung disease, diffuse alveolar hemorrhage, glomerulonephritis, COPA gene mutation, immunosuppression, sepsis, next-generation sequencing, type I interferon, follicular bronchiolitis, pulmonary-renal syndrome