RESUMEN

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a spectrum of autoimmune diseases, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Studies have shown that avacopan and mepolizumab are promising therapeutics for partial or complete replacement of glucocorticoids (GC), with sustained remission while completely weaning off GC. Avacopan inhibits C5aR in the complement pathway, preventing neutrophil migration, while mepolizumab targets IL-5R, reducing eosinophil activity. Additionally, complement inhibition has not only contributed to the recovery of renal function and alleviation of physical symptoms but has also enhanced patients' overall quality of life and mental well-being. This systematic review explores the pathogenesis of AAV, traditional treatments, and the potential of emerging complement and interleukin antagonist therapies such as avacopan and mepolizumab in revolutionizing AAV management.

RESUMEN

Systemic autoimmune diseases are complex conditions characterized by an immune system dysregulation and an aberrant activation against self-antigens, leading to tissue and organ damage. Even though genetic predisposition plays a role, it cannot fully explain the onset of these diseases, highlighting the significant impact of non-heritable influences such as environment, hormones and infections. The exposome represents all those factors, ranging from chemical pollutants and dietary components to psychological stressors and infectious agents. Epigenetics, which studies changes in gene expression without altering the DNA sequence, is a crucial link between exposome and the development of autoimmune diseases. Key epigenetic mechanisms include DNA methylation, histone modifications, and non-coding RNAs. These epigenetic modifications could provide a potential piece of the puzzle in understanding systemic autoimmune diseases and their connection with the exposome. In this work we have collected the most important and recent evidence in epigenetic changes linked to systemic autoimmune diseases (systemic lupus erythematosus, idiopathic inflammatory myopathies, ANCA-associated vasculitis, and rheumatoid arthritis), emphasizing the roles these changes may play in disease pathogenesis, their potential as diagnostic biomarkers and their prospective in the development of targeted therapies.

Asunto(s)

Enfermedades Autoinmunes , Metilación de ADN , Epigénesis Genética , Exposoma , Humanos , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/etiología , Animales

RESUMEN

Disease manifestations of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a small vessel vasculitis with multisystemic effects, include respiratory, renal, nervous, gastrointestinal, and skin implications. Muscle weakness and inflammatory myopathy are rare manifestations of AAV. We report the case of a 77-year-old female with a medical history of hypothyroidism and osteoarthritis who presented with a two-month history of worsening muscle weakness (mainly proximal). She endorsed dysphagia, a 40-lb unintentional weight loss, and persistent sinusitis with middle ear effusions, requiring bilateral tympanostomy. The physical examination was notable for 2/5 muscle strength in her hip flexors and extensors, with 4/5 strength in other extremities. Lower extremity MRI showed diffuse intramuscular edema between fat planes and intramuscular septal regions. Erythrocyte sedimentation rate (70 mm/hr), C-reactive protein (141 mg/L), creatine kinase (690 U/L), and anti-myeloperoxidase (MPO) antibodies (>999 AU/mL) were elevated. A thigh biopsy revealed fibrinoid necrosis of small intramuscular arteries, confluent circumferential granulomatous vessel wall inflammation, and associated mild chronic inflammation, including occasional eosinophils and a few plasma cells. She was diagnosed with MPO-positive AAV. The patient was started on high-dose steroids (prednisone), with a taper on a disease-modifying agent, azathioprine, with significant improvement in symptoms over the next four months and complete resolution at 16-month follow-up. This patient's clinical presentation of predominant lower extremity weakness due to inflammatory myositis is an unusual manifestation of AAV. Clinicians should keep a broad differential diagnosis and consider the possibility of AAV, especially in cases of muscle weakness presenting as inflammatory myositis, in the absence of other clinical manifestations of systemic vasculitis or specific myositis serologies.

RESUMEN

Microscopic polyangiitis (MPA) is predominantly characterized by rapidly progressive glomerulonephritis (RPGN) associated with myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). Nonetheless, up to 30% of cases of ANCA-associated vasculitis (AAV) may exhibit a more indolent progression toward renal failure, an aspect less frequently discussed and understood in medical literature. This study seeks to clarify the clinical and pathological distinctions between the slowly and rapidly progressive forms of MPA, thereby enhancing understanding of their distinct pathogeneses and treatment responses. We conducted a comparative analysis of two patients diagnosed with MPA under the 2022 American College of Rheumatology/the European Alliance of Associations for Rheumatology (ACR/EULAR) classification. Evaluations included laboratory tests such as serum creatinine levels, serology for MPO-ANCA, and renal biopsies. Patient 1 exhibited a mere 1.07% decrease in estimated glomerular filtration rate (eGFR) over 6 months, significantly below the RPGN threshold, and demonstrated sclerotic glomerular pathology without active inflammation. This patient also showed lower levels of MPO-ANCA, Birmingham Vasculitis Activity Score (BVAS), and C-reactive protein. Conversely, Patient 2 experienced an 89.9% reduction in eGFR over the same timeframe, accompanied by acute systemic inflammation. The comparative clinical analysis of these cases illuminates clear differences in disease activity. Slowly progressive MPA is marked by lesser disease activity that fosters chronic inflammation, leading to a more gradual decline in renal function. Early diagnosis, facilitated by initial measurements of MPO-ANCA, can enhance disease management and improve patient outcomes.

RESUMEN

INTRODUCTION: Despite advancements in managing autoimmune rheumatic diseases (ARDs) with existing treatments, many patients still encounter challenges such as inadequate responses, difficulty in maintaining remission, and side effects. Chimeric Antigen Receptor (CAR) T-cell therapy, originally developed for cancer, has now emerged as a promising option for cases of refractory ARDs. METHODS: A search of the literature was conducted to compose a narrative review exploring the current evidence, potential safety, limitations, potential modifications, and future directions of CAR-T cells in ARDs. RESULTS: CAR-T cell therapy has been administered to patients with refractory ARDs, including systemic lupus erythematosus, antisynthetase syndrome, and systemic sclerosis, demonstrating significant improvement. Notable responses include enhanced clinical symptoms, reduced serum autoantibody titers, and sustained remissions in disease activity. Preclinical and in vitro studies using both animal and human samples also support the efficacy and elaborate on potential mechanisms of CAR-T cells against antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. While cautious monitoring of adverse events, such as cytokine release syndrome, is crucial, the therapy appears to be highly tolerable. Nevertheless, challenges persist, including cost, durability due to potential CAR-T cell exhaustion, and manufacturing complexities, urging the development of innovative solutions to further enhance CAR-T cell therapy accessibility in ARDs. CONCLUSIONS: CAR-T cell therapy for refractory ARDs has demonstrated high effectiveness. While no significant warning signs are currently reported, achieving a balance between therapeutic efficacy and safety is vital in adapting CAR-T cell therapy for ARDs. Moreover, there is significant potential for technological advancements to enhance the delivery of this treatment to patients, thereby ensuring safer and more effective disease control for patients.

Asunto(s)

Enfermedades Autoinmunes , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Enfermedades Reumáticas , Humanos , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Enfermedades Reumáticas/terapia , Enfermedades Reumáticas/inmunología , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/inmunología , Receptores Quiméricos de Antígenos/inmunología

RESUMEN

We encountered a 64-year-old Japanese woman who developed subarachnoid hemorrhaging (SAH) with multiple cerebral artery stenoses during remission induction therapy for eosinophilic granulomatosis and polyangiitis (EGPA). The treatment involved intensified steroid pulse therapy and continued intravenous cyclophosphamide pulse therapy, which led to beneficial effects. Given the rarity of multiple EGPA-associated cerebral artery stenoses and SAH, it is crucial to differentiate them from other diseases. The mortality rate of EGPA complicated by intracranial hemorrhagic lesions, including SAH, is high. When headache is present at the onset of EGPA, the possibility of SAH must be considered.

RESUMEN

Hydralazine is a vasodilator medication commonly used for treating hypertension. While generally well-tolerated, in rare cases it can induce autoimmune reactions, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This case report presents a patient who developed ANCA-associated vasculitis resulting in crescentic glomerulonephritis (CrGN) following long-term hydralazine therapy, highlighting the importance of considering this rare adverse effect in patients with unexplained renal decline.

Asunto(s)

Agammaglobulinemia , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Humanos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Agammaglobulinemia/complicaciones , Agammaglobulinemia/inmunología , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/inmunología

RESUMEN

Antineutrophil cytoplasmic antibody-related vasculitis (AAV), is a group of diseases marked by systemic symptoms and severe small vessel inflammation. The three subtypes of AAV are eosinophilic GPA (EGPA), Microscopic Polyangiitis (MPA), and Granulomatosis with Polyangiitis (GPA). The organs that get involved in the disease process are the kidneys and the upper and lower respiratory tracts, with a spectrum of neurological manifestations. Here, we present a case report of a 68-year-old man who came with complaints of tingling and numbness over bilateral lower limbs for two months accompanied by difficulty in walking and bilateral foot drop without any respiratory complaints or involvement of sensory or autonomic system who was diagnosed with AAV (c-ANCA +) on further workup. A sural Nerve biopsy was done for confirmation which was suggestive of chronic, asymmetrical axonal neuropathy with perivascular inflammation, suggestive of vasculitic neuropathy. The patient had no other organ involvement. The patient was started on glucocorticoids and cyclophosphamide therapy for 6 cycles after which his symptoms and quality of life improved drastically.

RESUMEN

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic necrotizing vasculitis that affects small to medium-sized vessels. We describe two cases of patulous Eustachian tube (PET) in patients with otitis media with ANCA-associated vasculitis (OMAAV). The two cases presented in this paper had previously been diagnosed with Eustachian tube (ET) stenosis, and both presented with bilateral aural fullness, with one also experiencing postnasal drip and hearing loss. Both patients experienced positive myeloperoxidase (MPO)-ANCA and negative proteinase 3 (PR3)-ANCA, and treatment for ANCA-associated vasculitis (AAV) resulted in a diagnosis of PET. The patients were treated with transnasal self-installation of physiological saline into the pharyngeal orifice of the ET. This paper highlights the importance of considering PET in the differential diagnosis of OMAAV patients presenting with aural fullness.

RESUMEN

ANCA-associated vasculitis (AAV) can affect multiple organs with severe life-threatening manifestations. Disease monitoring is difficult due to a lack of defined biomarkers. We aimed to assess the diagnostic role of serum interleukin-6 and vascular ultrasonography in AAV and subclinical atherosclerosis. The study included 20 AAV patients and two control groups of 34 patients with rheumatoid arthritis (RA) and 35 healthy controls. The levels of Il-6, carotid intima-media thickness test (CIMT), atherosclerotic plaque, and degree of stenosis were investigated. A GRACE-risk score was calculated for AAV and RA patients. The AAV patients had elevated levels of IL-6 (115 ± 23.96) compared to the RA patients (91.25 ± 42.63) and the healthy controls (15.65 ± 3.30), p < 0.001. IL-6 showed a diagnostic accuracy of 73% in distinguishing AAV from RA patients (AUC = 0.730; 95% CI 0.591 to 0834). In the AAV group, CIMT was 1.09, above the upper reference value of 0.90, p < 0.001. The AAV patients had a higher median GRACE risk score, and 60% of them had a high risk of cardiovascular events as compared to 35% of the RA patients. Sonography of extracranial vessels and serum levels of IL-6 can be used in daily clinical practice to diagnose and monitor patients with AAV.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Artritis Reumatoide , Aterosclerosis , Biomarcadores , Grosor Intima-Media Carotídeo , Interleucina-6 , Humanos , Interleucina-6/sangre , Femenino , Masculino , Persona de Mediana Edad , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico por imagen , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Biomarcadores/sangre , Pronóstico , Adulto , Aterosclerosis/sangre , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/etiología , Aterosclerosis/diagnóstico , Anciano , Estudios de Casos y Controles , Arterias Carótidas/diagnóstico por imagen , Valor Predictivo de las Pruebas , Ultrasonografía de las Arterias Carótidas

RESUMEN

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis accompanied by granulomas and eosinophilic inflammation, exhibiting marked peripheral blood eosinophiliaandasthma. Neuropathy is a difficult-to-treat common manifestation that frequently remains after achieving clinical remission with current therapy in a subpopulation of patients with EGPA with or without life-threatening organ involvement. Refractory neuropathy regularly reduces the quality of life and requires glucocorticoids (GCs) and/or immunosuppressants for a long time. Long-term immunosuppressive therapy is a factor associated with a high risk of adverse effects. Mepolizumab, at three times the dose for severe asthma, provides benefits to induce the remission of relapsing or refractory EGPA and to reduce the doses of GC. Here, we present a case of EGPA successfully treated with mepolizumab at the reference dose for severe asthma. In this case, mepolizumab resolved peripheral neuropathy resistant to corticosteroids, immunosuppressants, and intravenous immunoglobulin and contributed to the improvement of comorbid chronic pulmonary aspergillosis during GC dose reduction.

RESUMEN

Vasculitis of the central nervous system can be a localized process, such as primary angiitis of the central nervous system (PACNS), or systemic vasculitis, such as ANCA-associated vasculitis (AAV). Since both conditions share neurological manifestations, the following review will discuss the neurological aspects of both. This review aims to provide a comprehensive comparison of the pathogenesis, clinical manifestation and assessment, diagnostic workup, and treatment protocol for both PACNS and AAV with central nervous system involvement. To provide a comprehensive comparison and update, a literature review was conducted using PubMed and Ovid databases (Embase and Medline). Then, the references were retrieved, screened, and selected according to the inclusion and exclusion criteria. PACNS and AAV share similarities in clinical presentation and neurological symptoms, especially in terms of headache, focal deficits, and cognitive impairment. Additionally, both conditions may exhibit similarities in laboratory and radiological findings, making brain biopsy the gold standard for differentiation between the two conditions. Moreover, the treatment protocols for PACNS and AAV are nearly identical. Comparing PACNS and AAV with CNS involvement highlights the similarities in clinical presentation, radiological findings, and treatment protocols between the two conditions. Further research should focus on establishing a practical diagnostic protocol.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Disfunción Cognitiva , Vasculitis del Sistema Nervioso Central , Humanos , Vasculitis del Sistema Nervioso Central/diagnóstico , Vasculitis del Sistema Nervioso Central/etiología , Vasculitis del Sistema Nervioso Central/terapia , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Sistema Nervioso Central

RESUMEN

OBJECTIVES: Antineutrophil cytoplasmic antibody (ANCA) testing assists clinicians diagnose ANCA-associated vasculitis (AAV). We aimed to verify and harmonize chemiluminescent immunoassays for the detection of myeloperoxidase (MPO)- and proteinase 3 (PR3)-ANCA. METHODS: An in-house ELISA, a capture ELISA, and a chemiluminescent assay QUANTA Flash on a BIO-FLASH analyzer were used to detect MPO- and PR3-ANCA in sera from 39 patients with AAV, 55 patients with various non-AAV, and 66 patients with connective tissue diseases. The results of the assays were evaluated, and their clinical performance was assessed. The precision and linearity of the QUANTA Flash assays were determined, and likelihood ratios (LRs) for AAV at diagnosis were calculated. RESULTS: The precision and linearity of the QUANTA Flash assays were confirmed. Overall agreement between 97.5 and 98.8 % and Cohen's kappa coefficients between 0.861 and 0.947 were observed for the results of the QUANTA Flash assays and ELISAs. The diagnostic sensitivity, specificity, and ROC analysis of the assays for AAV were statistically similar (in-house ELISA 89.7 %, 95.0 %, and 0.937; capture ELISA 92.3 %, 98.3 %, and 0.939; and QUANTA Flash 89.7 %, 95.9 %, and 0.972). For the QUANTA Flash assay results, the interval-specific LRs for AAV at diagnosis were: 0-8 CU had LR 0.08, 8-29 CU had LR 1.03, 29-121 CU had LR 7.76, 121-191 CU had LR 12.4, and >191 CU had LR ∞. CONCLUSIONS: The QUANTA Flash MPO and PR3 assays provide precise and consistent results and have comparable clinical utility for AAV. The calculated LRs were consistent with published LRs, confirming the utility of LRs for harmonization of ANCA results.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Humanos , Mieloblastina , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Ensayo de Inmunoadsorción Enzimática/métodos , Peroxidasa

RESUMEN

Avacopan, a C5a receptor antagonist (C5aR) presents a new therapeutic option to improve outcomes in ANCA-associated vasculitis (AAV). Here we present a case report of a patient initially requiring kidney replacement therapy (KRT), where avacopan was added as an additional adjunctive therapeutic agent late in the treatment course.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Ácidos Nipecóticos , Humanos , Granulomatosis con Poliangitis/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Riñón , Compuestos de Anilina/uso terapéutico , Anticuerpos Anticitoplasma de Neutrófilos

RESUMEN

The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and hematologic malignancy has been previously described and remains a rare phenomenon (although potentially underdiagnosed). We report the case of an 81-year-old patient with myelodysplastic syndrome who was managed for an infectious-appearing pneumonia, which subsequently complicated into complete heart block and severe acute respiratory distress syndrome with a fatal outcome. The final diagnosis is severe hemorrhagic alveolitis due to ANCA-associated vasculitis meeting the criteria for microscopic polyangiitis. This article provides an opportunity to discuss the association between ANCA-associated vasculitis and hematologic malignancies and the adverse prognosis associated with it.

RESUMEN

Peripheral neuropathy is a common manifestation of Eosinophilic Granulomatosis with Polyangiitis (EGPA), a rare autoimmune disorder caused by eosinophilic infiltration of multiple organs including the nervous system. Recent research has shown an association between myelin oligodendrocyte glycoprotein (MOG) antibodies and various neurologic conditions. We present a unique case of EGPA with positive MOG antibodies in the cerebrospinal fluid (CSF) in a patient presenting with peripheral neuropathy. We also highlight a few diagnostic dilemmas with EGPA and the importance of early diagnosis and appropriate treatment. Clinical, laboratory, radiological, and electrophysiologic findings are discussed.

RESUMEN

Granulomatosis with polyangiitis (GPA), formerly Wegener's granulomatosis, is a small- and medium-vessel vasculitis with characteristic cutaneous morphologic presentation and systemic involvement. Most patients have palpable purpura at some point in their disease course, but this is not always the presenting manifestation. This autoimmune disorder can affect a range of organs, with the upper and lower respiratory tract, kidneys, and nervous system being commonly implicated, while gastrointestinal and cardiac involvement is less frequent. This is a 44-year-old female presenting to the emergency department (ED) with polyarthralgia and palpable purpura. Palpable purpura was distributed on the oral palate, elbow, and lower back, and a punch biopsy revealed leukocytoclastic vasculitis (LCV). While this was an atypical distribution for leukocytoclastic vasculitis, the skin biopsy provided the necessary evidence to diagnose GPA. This case characterizes non-specific and atypical signs and symptoms of GPA that all providers should be aware of in order to diagnose the condition early in its disease course.

RESUMEN

Recent years have brought progress in understanding the role of the neutrophil, dispelling the dogma of homogeneous cells mainly involved in the prime defence against pathogens, shedding light on their pathogenic role in inflammatory diseases and on the importance of antineutrophil-cytoplasmic antibodies' pathogenic role in ANCA-associated vasculitides vasculitis (AAV). Myeloperoxidase (MPO) and proteinase 3 (PR3) expressed in neutrophil granulocytes are the most common targets for ANCAs and contribute to the formation of MPO-ANCAs and PR3-ANCAs which, released to the bloodstream, become an excellent diagnostic tool for AAV. In this study, we focus on increasing the clinical and experimental evidence that supports the pathogenic role of ANCAs in AAV. Additionally, we discuss the diagnostic utility of ANCAs for disease activity and prognosis in AAV. Understanding the central role of ANCAs in AAV is crucial for advancing our knowledge of these complex disorders and developing targeted therapeutic strategies in the era of personalized medicine.

Asunto(s)

Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Autoanticuerpos , Humanos , Neutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Peroxidasa , Mieloblastina

RESUMEN

Hydralazine-induced anti-neutrophil cytoplasmic antibody (ANCA) vasculitis may occur any time after hydralazine initiation. General internists should recognize diffuse alveolar hemorrhage (DAH) as a rare complication of this condition, as early treatment reduces the associated high risk of mortality. We describe the case of an 82-year-old female with diastolic heart failure who presented with a one-month history of worsening dyspnea on exertion and a one-week history of scant hemoptysis and fatigue. Her medications included aspirin and hydralazine. She was hypoxic with bilateral expiratory wheezes on exam. Labs showed new anemia, elevated creatinine, proteinuria, and hematuria. Chest computed tomography showed asymmetric bilateral upper lobe ground-glass attenuation superimposed on interlobular septal thickening and intralobular lines. Further testing showed anti-nuclear antibody, positive ANCA, perinuclear ANCA (p-ANCA), and anti-myeloperoxidase ANCA (anti-MPO-ANCA). Renal biopsy revealed MPO-ANCA, pauci-immune, necrotizing, and crescentic glomerulonephritis. She was diagnosed with DAH secondary to hydralazine-induced ANCA-associated vasculitis (AAV). Hydralazine is an anti-hypertensive medication with known potential for autoimmune reactions. Of these, AAV is a rare sequela mediated by anti-MPO and most commonly affects the kidneys. In rare circumstances, patients with AAV can develop pulmonary-renal syndrome, resulting in both glomerulonephritis and DAH with an associated high risk of mortality. Diagnosis requires a high index of suspicion in patients with acute kidney injury of unclear etiology. Early diagnosis through immune work-up and kidney biopsy should be pursued, as prompt recognition of the vasculitis, cessation of hydralazine, immunosuppression, and early plasma exchange are essential to an improved prognosis.