Large Vessel Vasculitis Research Articles

A Rare Case of Symmetrical Peripheral Gangrene in Central Venoarterial Extracorporeal Membrane Oxygenator in a Pediatric Patient, an Unusual Complication of Extracorporeal Membrane Oxygenation

Symmetrical peripheral gangrene is an unusual complication of extracorporeal membrane oxygenation (ECMO) which can arise due to low cardiac output state, high inotropic support, inadequate anticoagulation, disseminated intravascular coagulation, and sepsis. In symmetrical peripheral gangrene, there is no evidence of large vessel occlusion or vasculitis. It can be due to the absence of pulsatile flow in the peripheral arteries that result in stasis and microthrombi formation which causes occlusion of small arterioles. A 10-month-old male child who underwent anomalous left coronary artery from pulmonary artery repair and required central venoarterial ECMO support post-surgery due to severe myocardial dysfunction developed symmetrical peripheral ischemia with gangrenous changes in the right-hand fingers while on extracorporeal membrane oxygenation (ECMO). The limb ischemic changes improved to normal after the child convalesced from heart failure. We describe these changes and the management here.

Multiple systemic arterial aneurysms in large-vessel vasculitis

Large-vessel vasculitis (LVVs) is a rare inflammatory disease that predominantly affects young females' aorta and its main branches, coronary arteries, and pulmonary arteries. Clinical manifestations result from vascular stenosis, occlusion, and dilation, sometimes complicated by aneurysm rupture or dissection. Early diagnosis and treatment of LVVs are paramount to reducing the risk of ischemic complications such as visual loss and strokes, vascular stenosis and occlusion, and aortic aneurysm formation. The diagnosis of LVVs is often challenging because the presenting clinical features are nonspecific in many cases and are often shared by different types of autoimmune and inflammatory diseases including other systemic vasculitides. Prompt identification of vasculitides is important because they are associated with an increased risk of mortality. Left undiagnosed or mismanaged, these conditions may result in serious adverse outcomes that might otherwise have been avoided or minimized. We report a rare case of the LVVs with multisystemic vascular aneurysms and catastrophic complications of ruptured abdominal aortic aneurysm. Our case highlights that an early diagnosis of the diverse manifestations of vasculitis and a high index of clinical suspicion is essential to avoid delays in disease recognition that may result in permanent or life-threatening morbidity.

A case of Takayasu arteritis with normal coronary arteries presenting as stable angina

Takayasu arteritis (TAK) is a type of large vessel vasculitis characterized by granulomatous inflammation involving the aorta and its main branches. Clinical presentation may vary from non specific symptoms such as fever, malaise, weight loss to manifestations of organ hypo perfusion. Cardiac involvement may take forms of valvular insufficiency, angina or heart failure. In this case, we report a 39-year-old woman with hypertension presenting with angina, who was found to have multiple arterial bruits, with blood pressure and pulse volume discrepancies, aortic regurgitation and renovascular hypertension. She was diagnosed with Takayasu arteritis with clinical and imaging criteria; managed with glucocorticoid and DMARDS, achieving good clinical response and planned for surgical intervention for valvular insufficiency.

New imaging strategy for large vessel vasculitis (based on the EULAR-2023 recommendations)

Large vessel vasculitis (LVV), including Takayasu's arteritis (AT, or non-specific aortoarteritis) and giant cell arteritis (GCA), is caused by granulomatous inflammation affecting mainly the aorta and its main branches. Damage to the vascular wall leads to ischemia of the corresponding organs and can be complicated by loss of vision, cerebral insufficiency and other life-threatening phenomena. The early diagnosis of these diseases in clinical practice is a difficult task that can only be solved by comparing the clinical symptoms, the results of the physical, laboratory and instrumental examination and the vascular biopsy.A comparative analysis of the 2018 and 2023 EULAR recommendations for imaging in LVV is presented. Duplex ultrasound (USDS) of not only temporal but also axillary arteries is recommended for GCA and magnetic resonance imaging (MRI) for AT. Alternative methods for GCA are MRI or positron emission tomography (PET) in combination with computed tomography (CT) and intravenous administration of fluorodeoxyglucose labelled with the short-lived fluoride isotope 18 (FDG-PET/CT), and for AT – FDG-PET/CT, CT or ultrasound examination. MRI, CT or ultrasound can be used for long-term monitoring of structural damage, especially to assess pre-existing vascular inflammation.

Advances and challenges in management of large vessel vasculitis.

Glucocorticoids (GC) remains the mainstay for management of large vessel vasculitis (LVV). Recent introduction of interleukin-6 signaling blocker, tocilizumab has substantially changed the practice in management of patients with LVV, in particular, giant cell arteritis (GCA). Benefit of tocilizumab to patients with Takayasu arteritis (TAK) is supported by observational studies, but randomized clinical trials are lacking. Addition of tocilizumab enables reduction of the total amount of GC in patients with GCA, but GC burden remains high and to be further reduced. Ongoing studies aim at minimal use of GC or even GC-free. Tumor necrosis factor inhibitors appear to be beneficial to TAK despite their ineffectiveness to GCA. Randomized clinical trials are undergoing to target other inflammatory cytokines in both GCA and TAK. Janus kinase inhibitors alone or in combination with conventional disease modifying anti-rheumatic drugs showed promising results in treatment of TAK.

Large-Vessel Vasculitis and Q Fever Correlation.

Large-vessel vasculitis is a possible immunologic response to acute Q fever infection.There are few data about the management and treatment of patients with Q fever related large-vessel vasculitis.

Unveiling the Silent Constrictor: A Case Report of Takayasu Arteritis Manifesting as a Vascular Enigma

Introduction
 Takayasu arteritis (TKA) is a rare large vessel vasculitis, most prevalent in Asia and affecting females ages 10-40 years. Through unclear etiology, it triggers chronic granulomatous inflammation leading to vessel wall thickening, stenosis, and occlusion. Manifestations vary from mild malaise to severe ischemic complications. Diagnosis hinges on clinical criteria, including angiography, and exclusion of mimicking conditions like giant cell arteritis, fibromuscular dysplasia, or atherosclerosis. Treatment necessitates immunosuppression and anti-inflammatories to curb disease progression and limit complications.
 Case Presentation
 A 61-year-old Caucasian female presented with claudication of the upper extremities upon using the shower. She reported episodes of headache, myalgia, fever and chills of several months. She reported fatigue with overhead reaching and difficulty finding her pulse on her upper extremities. Labs were notable for elevated ESR and CRP. MRA chest showed smoky thickened appearance of the descending aorta wall, some missing wall thickening in origins of the left common carotid and left subclavian arteries. PET scan revealed diffuse hypermetabolic activity involving the bilateral common carotid arteries, peripheral aortic arch and descending thoracic aorta (Figure 1). With these ongoing symptoms and characteristic features on imaging, we established the diagnosis of TKA. She was started on 5mg oral prednisone daily and methotrexate 10mg weekly with daily folic acid.
 Conclusion
 This case highlights the diagnosis and treatment of a rare condition, Takayasu arteritis, the pulseless disease. TKA is a challenging condition to study and understand fully, but advancements in medical knowledge, imaging, and management are gradually improving our understanding and ability to diagnose and treat this condition. With increased awareness of this condition, earlier detection and monitoring will serve to benefit future patient populations.

Molecular imaging of large vessel vasculitis

Large vessel vasculitis (LVV) affects mainly large arteries with giant cell arteritis (GCA) and Takayasu arteritis (TAK) being the two most frequent forms. Clinical symptoms can be non-specific, including headache, fatigue, weight loss, and change in vision. Untreated, LVV may also lead to serious complications such as blindness, aortic aneurysm and dissection. Therefore, rapid recognition of the disease leading to accurate diagnosis and appropriate treatment is essential. FDG-PET/CT imaging has emerged as a sensitive marker of active vascular inflammation and its use in the management of LVV is now integrated in guidelines. In this article, we will discuss the role of FDG-PET/CT for the diagnosis of LVV and monitoring of therapy, as well as review technical and interpretation parameters.

Ischemic injury of colon mucosa as a first manifestation of Takayasu arteritis in a young female patient: challenges in the differential diagnosis

Takayasu arteritis (TA) is a type of chronic large vessel vasculitis, which most often affects the aorta and its main branches as a kind of destructive-productive segmental aortitis and subaortic panarteritis, with possible obliteration of their orifices. Clinical picture of TA may be different depending on the nature and localization of the pathological process.
 We present a clinical case of ischemic injury of the colon mucosa in TA in a young (21 year old) female patient after she had a novel coronavirus infection (COVID-19). Due to ineffectiveness of out-patient treatment of ulcerative colitis, as well as complaints that were not meeting the diagnosis of ulcerative colitis, the patient was referred for additional examination and treatment modification in inpatient settings. Taking into account her diarrheal syndrome at the disease onset, the ileocolonoscopy results (rectal and colonic erosions), the results of histological examination (diffuse leukocytic infiltration of the mucosa, lymphoid infiltration of submucosa of the colon), elevation of proinflammatory markers, involvement of the inferior mesenteric artery at ultrasound dopplerography, the differential diagnosis was made between the TA overlap syndrome with inflammatory bowel diseases and TA-associated ischemic colitis. The assessment results made it possible to exclude inflammatory bowel diseases, to establish the diagnosis of TA and to consider colonic mucosa abnormalities as ischemic with underlying disease.
 The clinical case described is a rare event of intestinal ischemia as a first TA manifestation. Given the increasing worldwide prevalence of TA, especially after the new coronavirus infection pandemic, it is necessary to include this rare cause of gastrointestinal vasculitis to the differential diagnostic search, since mesenteric ischemia is one of the main causes of death in AT patients.

Characterising polymyalgia rheumatica on whole-body 18F-FDG PET/CT: an atlas.

The impact of modern imaging in uncovering the underlying pathology of PMR cannot be understated. Long dismissed as an inflammatory syndrome with links to the large vessel vasculitis giant cell arteritis (GCA), a pathognomonic pattern of musculotendinous inflammation is now attributed to PMR and may be used to confirm its diagnosis. Among the available modalities, 18F-fluorodeoxyglucose (18F-FDG) PET/CT is increasingly recognized for its high sensitivity and specificity, as well as added ability to detect concomitant large vessel GCA and exclude other relevant differentials like infection and malignancy. This atlas provides a contemporary depiction of PMR's pathology and outlines how this knowledge translates into a pattern of findings on whole body 18F-FDG PET/CT that can reliably confirm its diagnosis.

Clinical value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography combined with computed tomography angiography in large-vessel vasculitis

Abstract OBJECTIVES: The objectives of this study were to investigate the clinical application of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) combined with CT angiography (CTA) fusion images at diagnosis and assessment in large-vessel vasculitis (LVV). MATERIALS AND METHODS: Forty-six patients with LVV who underwent both 18F-FDG-PET/CT and CTA procedures were studied in the Second Hospital of Harbin Medical University from September 2019 to June 2022, and the clinical disease activity of patients was judged by the Physician Global Assessment. Clinical data, acute-phase reactants (APRs), and imaging data were collected. Meanwhile, the APRS must be obtained within 1 week of 18F-FDG-PET/CT. 18F-FDG-PET/CT was primarily used to evaluate LVV activity, while CTA was primarily used to observe morphological changes in arteries, including arterial wall thickening, narrowing, and corresponding complications. PET/CT images were evaluated by two nuclear medicine physicians, both of them unaware of the patients’ laboratory tests and clinical signs. Two nuclear medicine specialists evaluated the PET/CT images and PET/CTA images, who were blinded to the patients’ information. The concordance of two physicians in the LVV visual grading scale was studied by calculating the Cohen’s kappa index (k) which evaluates the power of concordance. The paired t-test was used to analyze the differences between PET/CTA images and PET/CT images. RESULTS: The sensitivity and specificity of the semi-quantitative analysis to assess LVV activity was 94.1% and 93.1%, respectively, when a cutoff of the mean SUVmax/SUVmeanliver of 1.15. It was found that the images obtained after delayed phase were clearer and the contrast between the arterial wall and the lumen was higher in 19 patients. We also concluded that PET/CTA examinations were able to detect more lesion sites compared to PET/CT examinations in 28 patients (P < 0.001), especially for patients with long-term treatment, and the interpretation of PET/CTA images took less time than PET/CT images(P < 0.001), ultimately achieving a shorter time, more comprehensive and accurate interpretation. CONCLUSION: Although 18F-FDG-PET/CT can assess the activity of LVV, it is poor at observing morphological changes in arteries. The use of 18F-FDG-PET/CTA imaging scans in LVV can accurately assess disease activity while at the same time providing a comprehensive, accurate, and efficient determination of disease severity, allowing patients to receive comprehensive diagnostic information from PET/CTA examination.

Atypical Cogan's Syndrome with Large-vessel Vasculitis Successfully Treated with Tocilizumab.

A 61-year-old man presented with weight loss, bilateral ocular redness, blurred vision, and sensorineural hearing loss. Fluorodeoxyglucose-position emission tomography/computed tomography demonstrated an uptake in the ascending and descending aorta, abdominal aorta and femoral arteries. Atypical Cogan's syndrome complicated with large-vessel vasculitis (LVV) was diagnosed. He was treated with high-dose prednisolone and subcutaneous tocilizumab (162 mg/week), resulting in successful improvements in his ocular and vascular involvements. Although there is currently no established treatment strategy for LVV associated with Cogan's syndrome, our case and literature review suggest that tocilizumab is a viable treatment option for this rare but life-threatening complication.

Vasculitis distribution and clinical characteristics in giant cell arteritis: a retrospective study using the new 2022 ACR/EULAR classification criteria.

Giant cell arteritis (GCA) is the most common vasculitis of the elderly. In recent years, advanced imaging has to a certain extent replaced temporal artery biopsy (TAB) to aid diagnosis in many institutions and helped to identify three major phenotypes of GCA, namely, cranial GCA (c-GCA), large-vessel non-cranial GCA (LV-GCA), and a combination of these two patterns called mixed-GCA, which all show different clinical patterns. Recent 2022 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria respect the changing conception and clinical practice during the last two decades. In this cohort study, we present vasculitis distribution and baseline characteristics using the 2022 ACR/EULAR classification criteria as well as the EULAR core data set. In this retrospective study from Southern Norway, we identified all patients diagnosed with GCA between 2006 and 2019 in our single-center fast-track clinic (FTC). We included all patients who were examined using ultrasound (US) of cranial as well as non-cranial large vessels at diagnosis to depict vascular distribution. EULAR core data set, ACR 1990, and 2022 ACR/EULAR classification criteria were used to characterize the cohort. Seventy-seven patients were diagnosed with GCA at our institution in the aforementioned period. Seventy-one patients (92.2%) were diagnosed with the help of US and included in the further analysis. The 2022 ACR/EULAR classification criteria allocated 69 patients (97.2%), while the ACR 1990 classification criteria allocated 49 patients (69.0%) in our cohort as having GCA. Mixed-GCA was the most common type in 33 patients (46.5%). Weight loss was significantly more common in patients with large-vessel non-cranial vasculitis in LV-GCA and mixed-GCA. Headache, on the other hand, was significantly more common in patients with involvement of cranial vessels. Mixed GCA was the most common form of GCA in our cohort. In our study, the 2022 ACR/EULAR classification criteria seem to be a more useful tool compared with the old ACR 1990 classification criteria to allocate GCA patients diagnosed and treated at our US-based FTC as having GCA.

Large-vessel vasculitis in an elderly patient with recurrent coronary stent stenosis detected by fluorodeoxyglucose positron emission tomography.

Large-vessel vasculitis in an elderly patient with recurrent coronary stent stenosis detected by fluorodeoxyglucose positron emission tomography.

The Role of PET in the Diagnosis and Disease Activity Assessment in Large Vessel Vasculitis

The role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (18F-FDG PET) in the diagnosis of large vessel vasculitis (LVV) is well established. It permits us to assess the extent and the grade of vascular involvement and to rule out the other causes in clinical scenarios characterized by less specific symptoms. The advantages of 18F-FDG PET are far less clear in monitoring disease activity over time. Studies looking for the role of 18F-FDG PET as a potential biomarker had conflicting results and whether and when to repeat it during follow-up is based on clinical experience. A comprehensive assessment, including clinical, laboratory and morphological imaging is still required to monitor patients with large-vessel vasculitis over time. The aim of this review is to present more recent data about the utility of 18 F-FDG PET in the diagnosis and follow-up of LVV.

Beyond the symptoms: Personalizing giant cell arteritis care through multidimensional patient reported outcome measure

BackgroundGiant Cell Arteritis (GCA) is the commonest form of systemic vasculitis in people over the age of 50. Published research highlighted the lack of a disease-specific patient reported outcomes (PROMs) for GCA. ObjectivesTo assess the validity, reliability and responsiveness to change of a devised disease specific patient self-reported outcome measures questionnaire for Giant Cell Arteritis (GCA). MethodsThe GCA-PROMs was conceptualized based on frameworks outlined in the OMERACT developed core set of Outcome Measures for Large-Vessel Vasculitis and the guiding principles of the FDA guidance. Initially, cognitive interviews were conducted to identify item pool of questions. Item selection and reduction was achieved based on patients as well as an interdisciplinary group of specialists. Rasch and internal consistency reliability analyses were implemented. ResultsA total of 54 GCA patients completed the questionnaire. The GCA-PROMs questionnaire was reliable as demonstrated by a high standardized alpha (0.878–0.983). Content construct assessment of the GCA-PROMs functional disability and QoL revealed significant correlation (p< 0.01) with both HAQ and EQ-5D. Changes in functional disability, QoL showed significant (p< 0.01) variation with diseases activity status in response to therapy. ConclusionsThe developed GCA-PROMs questionnaire is a reliable and valid instrument for assessment of GCA patients. A stratified treatment regimen depending on the individual patient's risk factors as well as preferences and associated comorbidities is the best approach to tailored patient management.

Philadelphia chromosome-negative myeloproliferative chronic neoplasms: is clonal hematopoiesis the main determinant of autoimmune and cardio-vascular manifestations?

In this article, we reviewed the possible mechanisms linking the clonal hematopoiesis of indeterminate potential (CHIP) to chronic myeloproliferative neoplasms (MPNs), autoimmune diseases (ADs), and cardiovascular diseases (CADs). CHIP is characterized by the presence of clonal mutations with an allelic frequency >2% in the peripheral blood without dysplasia, overt hematological neoplasms, or abnormalities in blood cell count. The prevalence may reach 20% of elderly healthy individuals and is considered a risk factor for myelodysplastic neoplasms and acute leukemia. In MPNs, CHIP is often associated with mutations such as JAK2V617F or DNMT3A, TET2, or ASXL1, which exhibit a 12.1- and 1.7-2-fold increase in CADs. Specifically, JAK2-mutated cells produce excessive cytokines and reactive oxygen species, leading to proinflammatory modifications in the bone marrow microenvironment. Consequently, the likelihood of experiencing thrombosis is influenced by the variant allele frequency (VAF) of the JAK2V617F mutation, which also appears to be correlated with anti-endothelial cell antibodies that sustain thrombosis. However, DNMT3A mutations induce pro-inflammatory T-cell polarization and activate the inflammasome complex, while TET2 downregulation leads to endothelial cell autophagy and inflammatory factor upregulation. As a result, in patients with TET2 and DNMT3A-related CHIP, the inflammasome hyperactivation represents a potential cause of CADs. CHIP also occurs in patients with large and small vessel vasculitis, while ADs are more frequently associated with MPNs. In these diseases, monocytes and neutrophils play a key role in the formation of neutrophil extracellular trap (NET) as well as anti-endothelial cell antibodies, resulting in a final procoagulant effect. ADs, such as systemic lupus erythematosus, psoriasis, and arthritis, are also characterized by an overexpression of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a serine/threonine kinase that can hyperactivate the JAK-STAT pathway. Interestingly, hyperactivation of ROCK2 has also been observed in myeloid malignancies, where it promotes the growth and survival of leukemic cells. In summary, the presence of CHIP, with or without neoplasia, can be associated with autoimmune manifestations and thrombosis. In the presence of these manifestations, it is necessary to consider a "disease-modifying therapy" that may either reduce the clonal burden or inhibit the clonally activated JAK pathway.

Сarotid artery ultrasonography for diagnosis and monitoring of cervical and intracranial large vessel vasculitis in a patient with systemic lupus erythematosus and Sjögren syndrome.

Сarotid artery ultrasonography for diagnosis and monitoring of cervical and intracranial large vessel vasculitis in a patient with systemic lupus erythematosus and Sjögren syndrome.

Large Vessel Vasculitis with Chronic Cough.

Large Vessel Vasculitis with Chronic Cough.

OA18 Small vessel and large vessel vasculitis due to rheumatoid vasculitis: a case of mononeuritis multiplex with pulseless foot leading to amputation

Abstract Introduction Rheumatoid vasculitis occurs in patients with longstanding severe seropositive rheumatoid arthritis. The incidence has reduced drastically with availability of more effective medication. Rheumatoid vasculitis primarily affects small and medium vessels, and rarely large vessels as well. Case description This 77-year-old lady with deforming seropositive rheumatoid arthritis was stable on methotrexate under the care of multiple Trusts for the last 30 years. Methotrexate had been stopped a year ago due to pancytopenia and she was started on prednisolone and hydroxychloroquine. While on these medications she flared with arthralgia and had difficulty in walking attributed to ankle synovitis. She was started on adalimumab, after 3 doses of which she developed widespread skin psoriasis leading to discontinuation. Subsequently, she was admitted to our Trust with left foot gangrene and was referred to rheumatology. Further questioning revealed that numbness in both lower limbs, inability to walk and frequent falls had started following the cessation of methotrexate. On examination, there was bilateral foot drop, worse on the right side. The left foot was gangrenous with diminished pulses in dorsalis pedis and posterior tibial arteries with preserved all other pulses. There was no vasculitic rash or nail fold infarcts. Psoriatic rash had resolved and there was no active synovitis in the joints. Nerve conduction test revealed severe ongoing axonal degenerative type sensory and motor polyneuropathy in the lower limbs without any upper limb involvement. CT angiogram showed multifocal stenoses, more so in the left common iliac, external iliac and superficial femoral artery. There were no conventional vascular risk factors such as hypertension, diabetes, dyslipidaemia or smoking, and there was no past history of cardiovascular disease. PET-CT scan did not reveal any features of vasculitis or aortitis. The vasculitis screening was negative including cryoglobulins. Initially she was on IV antibiotics for left foot cellulitis, hence she was managed with steroids without any potent immunosuppressive agents. Subsequently, she underwent left sided below knee amputation. After the wound had healed, she was started on IV rituximab with low-dose methotrexate and steroid taper. Discussion Although rare, rheumatoid vasculitis can cause significant morbidity and complications. Rheumatoid vasculitis tends to occur in patients with so-called ‘burnt-out’ RA and strongly associated with seropositivity. While it can affect many organ systems, skin and the peripheral nervous system are most frequently affected. Cutaneous vasculitis occurs in around 90% of patients and is the most common clinical manifestation. This includes parable purpura, leg ulcers and nailfold infarcts. It may lead to digital ischaemia, necrosis and gangrene if large vessels are involved. Another common manifestation is a vasculitic neuropathy due to involvement of the vaso nervorum. Around 40% have a sensory neuropathy and 20% have a mixed sensory motor neuropathy like the index patient. Ocular manifestations such as scleritis have been described and may be the first indication of rheumatoid vasculitis. Aortitis in rheumatoid vasculitis may present with aortic insufficiency and aneurysm formation. Pericarditis has also been described as a possible disease manifestation in patients with rheumatoid vasculitis. Our patient did not have any of these clinical features and the PET-CT scan was unremarkable, which could have been due to the steroids she was on prior to the scan. Clinically, there was pulseless gangrene of the left foot with CT angiogram showing multiple stenosis suggesting large vessel involvement in the absence of conventional vascular risk factors. Renal involvement in rheumatoid vasculitis is very rare. PAN like renal involvement and glomerulonephritis has been described. Our patient did not have any haematuria or any significant proteinuria, and imaging did not reveal any renovascular aneurysms. Isolated nailfold infarcts do not require any systemic treatment. Systemic involvement with rheumatoid vasculitis requires aggressive treatment with high-dose steroids with cyclophosphamide or rituximab. Our patient had neuropathy and gangrene of the left foot, hence she was started on rituximab accordingly. Key learning points Rheumatoid vasculitis is a rare but serious complication which can present with a vasculitic neuropathy/mononeuritis multiplex. Rarely, it can cause ischemia and gangrene. If there is systemic involvement, aggressive therapy with steroids, cyclophosphamide or rituximab is needed.