The Efficacy of Medium- to Long-term Anti-TNF-α Antibody-based Maintenance Therapy in Behçet's Disease Patients with Intestinal Lesions
Harutaka KambayashiTeppei OmoriSatomi SaitoShun MurasugiHiroyuki KashiwagiAyumi ItoMaria YonezawaShinichi NakamuraKatsutoshi Tokushige
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Abstract:
Objective Anti-tumor necrosis factor (TNF)-α antibody-based regimens are effective in Behçet's disease (BD) with intestinal lesions. We therefore evaluated the efficacy of medium- to long-term anti-TNF-α antibody-based maintenance therapy of BD intestinal and non-intestinal lesions.Keywords:
Antibody therapy
Maintenance therapy
Behcet disease
This review discusses recent scientific developments in the diagnosis, treatment, and prognosis of intestinal Behçet's disease.Gastrointestinal involvement is a major cause of morbidity and mortality in Behçet's disease. Patient clinical data are scarce because of the rarity of the disease; however, novel diagnostic criteria and disease activity indices have been developed recently to aid treatment of Behçet's disease patients. Current therapies include 5-aminosalicylic acids, corticosteroids, immunomodulators, or antitumor necrosis factor alpha agents. Antitumor necrosis factor alpha agents can achieve clinical responses and remission in patients that were previously nonresponsive to corticosteroids or immunomodulators. Clinical variables, including young age and higher disease activity at the time of diagnosis, volcano-type ulcers, absence of mucosal healing, higher C-reactive protein levels, prior history of surgery, and lack of initial response to medical therapy, can be regarded as poor prognostic factors.Previously, the diagnosis and management of intestinal Behçet's disease depended upon the expertise of individual clinicians; however, more standardized medical assessments and improved treatment regimens for Behçet's disease patients are evolving.
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Annotation. The article presents a description of the observation of a patient with Behcet’s disease, a rare systemic disease. The description traces the stages of disease development, difficulties in its diagnosis, polymorphism. The publication also presents modern views on the etiology, mechanisms of occurrence, diagnosis and consequences of Behcet's disease.
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Behcet's disease is a chronic vasculitis disease,characterized by recurrent oral mucosal ulcer and can involve many systemic manifestations including genital ulcer,ocular disease,skin lesions,neurologic disease,vascular disease and arthral disease.
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Behcet's disease (BD) is a rare multisystem chronic vasculitis of variable clinical presentation and unknown origin. Pulmonary involvement in BD is uncommon, with pleural effusion being an even rarer and difficult to diagnose manifestation. Herein, we report a challenging case of a young man who presented with recurrent pleural effusion and hepatic vein thrombosis and a recent history of papilledema with idiopathic intracranial hypertension. The patient was hospitalized for diagnostic and therapeutic thoracocentesis. Biochemistry and cytological analysis showed an exudative aspect of the collected pleural fluid with lymphocyte-dominated cytology. A multidisciplinary discussion was held, and thorough investigation was carried out to rule out malignant and infectious etiologies, among other differentials. During the second hospitalization, the patient complained of genital ulcers, which were verified to be recurrent along with oral ulcers. The diagnosis of BD was established based on the International Classification Criteria for BD, and the symptoms improved significantly upon using colchicine and immune-suppressive drugs.
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Objective To better explore the condition of diagnosis and treatments of Neuro-Behcet's disease in domestic Methods The diagnosis and treatments,and the follow-up of two cases with typically Neuro-Behcet's disease were observed.Data were extracted and then analyzed.Results The treatment for patients was effective by normally using steroids and immunosuppressant.Conclusions Neuro-Behcet's disease is mainly diagnosed by clinical symptoms and imageology.Since there is no uniform and specific standards in domestic now,the treatment of Neuro-Behcet's disease is mainly referring to the use of adrenocorticosteroids and immunosuppressant.
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Behcet’s disease is a multisystem autoimmune disease with variable clinial manifestations. The diagnosis may pose a difficult challenge for the clinician, who has to be familiar with the wide spectrum and combination of the symptoms of Behcet’s disease. It is considered a rare disease in Hungary, and there are only few reports on Behcet’s disease in the Hungarian literature. However, the past history of Hungary, the worldwide growing incidence of the disease, and the authors’ experience raise the possibility that the occurrence of the disease is higher than previously thought. In this review the authors present and discuss literature data on the pathogenesis and pathomechanism, as well as their own experience concerning the symptomatology of Behcet’s disease in order to promote diagnosis and offer adequate therapy for the patients. The authors presume that the importance of the disease is underestimated in Hungary due to a considerable number of unrecognized cases and they propose to establish a national registry for Behcets disease. Orv. Hetil., 2013, 154, 93–101.
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Dear Editor, A 70-year-old man began to suffer from recurrent manifestations of aphthous stomatitis. Erythema nodosum and pseudofolliculitis began to appear on the legs and face, with repeated spontaneous remission and recurrence. They were occasionally accompanied by fever. With a positive pathergy test, he was diagnosed with Behcet's disease (BD) based on the revised international criteria for BD.1 His human leukocyte antigen (HLA) typing was A24, B35, B75. Because his symptoms were mild, nonsteroidal anti-inflammatory drugs (NSAIDs), topical glucocorticoids and topical analgesics were given in compliance with his wishes. As for laboratory results, mild normocytic anemia with a hemoglobin (Hb) level of 9–10 g/dL was continuously observed, which was attributed to recurrent inflammatory attacks. After the mild clinical course had lasted for 6 years, the patient came to the emergency room because of a sudden episode of hematemesis. Hb had dropped from 10.1 g/dL at the last visit to 5.8 g/dL and his blood pressure was 94/50 mmHg, accompanied by tachycardia. Gastric endoscopy identified pulsating bleeding from a sharply demarcated gastric ulcer (Fig. 1a), for which hemostasis was achieved by ethanol injection and clipping. The second-look endoscopy performed on the next day confirmed the hemostasis; in addition, two small ulcers with a round, sharply demarcated border were seen in the lower esophagus (Fig. 1b), which were morphologically consistent with BD.2 Their relevant differential diagnoses, gastric acid-induced ulcer, microorganism infection and retention of certain drugs, were unlikely. Thus, although gastric ulcer development can be attributed to the occasional use of NSAIDs, gastrointestinal (GI) BD was suspected from the overall clinical picture of the ulcers. All the ulcers healed with bowel rest, a special diet and the use of proton pump inhibitors. After anemia had been treated, the patient was discharged. Three months later, he visited the emergency room again with a complaint of severe dyspnea. Close examination showed that he had left-sided heart failure, which had developed in association with severe anemia. The complete blood count was: white blood cell (WBC) 3800/μL (neutrophils 2500, lymphocytes 1000); hemoglobin 5.5 g/dL; and platelets 21.5 × 104/μL. The ulcers had almost healed on gastric endoscopy; furthermore, no abnormality on colon endoscopy or iron deficiency on a blood test was observed. To investigate the cause of severe anemia, bone marrow examination was performed, which revealed morphological abnormalities in all three lineages with a mild increase of blasts (7%). He was diagnosed with myelodysplastic syndrome (MDS)-refractory anemia with an excess of blasts (RAEB)-1. Chromosome banding revealed a complicated karyotype: 45XY, add(2)(q11.2), der (2)add(2)(p11.2)add(2)(q33), -5, add(6)(q21), add(7)(p11.2). Considering his advanced age and expected poor prognosis, supportive therapy such as blood transfusions was selected. Four months later, the patient came to the emergency room because of bloody stools. His vital signs were near a shock state. Emergent colon endoscopy revealed multiple small ulcers in the terminal ileum (Fig. 1c) and an ileocecal, sharply-demarcated, bleeding ulcer with an exposed vessel (Fig. 1d), which were typical lesions of GI BD.3 Intestinal tuberculosis, nonspecific chronic ulcers of the small intestine and lymphoma were considered as differential diagnoses, but they were unlikely, judging from the clinical course and other laboratory and radiological examinations. Clipping of the vessel achieved hemostasis. Because severe bleedings due to GI BD successively occurred within 6 months, specific treatment was thought to be required. After prednisolone (PSL) at 60 mg/day was given for 3 days, PSL at 20 mg/day was used for 1 month. Then the dose was gradually tapered (Fig. 2). No recurrence of GI disease was observed thereafter. While blood transfusion was regularly performed in ambulatory care in this case, blasts in the peripheral blood began to increase and bone marrow aspiration confirmed that MDS had progressed to overt leukemia after 8 months. Subsequently, he showed repeated pulmonary infections and finally died of multiple organ failure. MDS is a clonal hematologic disease characterized by blood cell dysplasia. Various autoimmune diseases, including vasculitis of the skin, polyarthritis and peripheral neuropathy, have been reported to be associated with MDS.4-7 The frequency of autoimmune disease among MDS patients was estimated to be about 15%. In most cases, autoimmunity was diagnosed concurrently with MDS.4, 5 How MDS and autoimmunity are related is yet to be clarified, but studies have shown a variety of immunological dysfunctions in MDS patients, which may lead to the development of autoimmune diseases.4, 5 Among autoimmune diseases, a certain type of BD has been reported to develop in association with MDS. These patients were mostly reported from Japan, with their clinical hallmark being a frequent occurrence of GI disease, while the frequency of eye disease or disease-specific HLA-B51 was lower than that of BD patients.8-10 As for MDS, early-stage MDS, such as refractory anemia and refractory anemia with ringed sideroblasts, was the most common, but the ratio of each MDS type was nearly equivalent to that reported in all MDS patients in Japan.11 The reported MDS was usually diagnosed before or concomitantly with BD. Regarding GI disease, detailed descriptions are scarce, but the information available in the English literature suggested that GI disease in BD patients with MDS has similar features to that in solely BD patients;8-10 for example, most of them had terminal ileum ulcers and some suffered from severe bleeding. Our case report is valuable in that we described the detailed course of GI disease, which was closely related to the progression of MDS. Furthermore, only 10 cases, including ours, have been reported to show both esophageal and ileocolonic ulcers12 and this is the first case among BD patients with MDS. Pathologically, BD and MDS share many immunopathological features: increased levels of inflammatory cytokines represented by tumor necrosis factor (TNF) alpha and interleukin (IL)-6 and an enhanced response of proinflammatory Th1 and Th17 subsets have been reported.13, 14 In our patient BD seemingly preceded MDS, but it is difficult to detect MDS in asymptomatic patients. Chronic mild anemia, which had been initially attributed to the chronic inflammation of BD, might have been due to asymptomatic myelodysplasia. Furthermore, the occurrence of GI disease coincided with the progression of MDS-related anemia. A diagnosis of RAEB-1 was made, but a relatively rapid worsening of anemia inferred the progression of MDS, from an early stage to the advanced one. Although the proinflammatory immune response is enhanced in all stages of MDS, it has been reported that the pattern differs between early and late stages; for example, IL-6 production and the TNF alpha-producing Th22 response were shown to be enhanced in late-stage MDS.14 This shift in the immunological background might have led to the aggravation of BD. Intriguingly, this hypothesis is consistent with the studies by Dalamaga and Okamoto, which showed that autoimmunity tends to occur in late-stage MDS and is associated with a poor prognosis.6, 7 As another hypothesis, neutrophils originating from a hematopoietic cell with an abnormal chromosome might have altered the function and affected the activity of BD, as neutrophils play a pivotal role in its pathogenesis.9 In the gradually aging society, MDS-related autoimmune disease is expected to be more common in accordance with the increased incidence of MDS. As the pathology of MDS-related BD is gradually becoming more closely understood owing to its characteristic nature, the accumulation of more experience with the disease is expected to help understand the overall clinical picture of MDS-related autoimmunity. The authors declare there is no conflict of interest.
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A 35-year-old male patient presented to the wound care outpatient clinic with a wound in his right ankle which had appeared 3 months ago. He had an ulcer at the upper part of the lateral malleolus on the right ankle with a size of 3 × 2 cm2 (Figure 1). Venous Doppler ultrasound revealed findings consistent with venous insufficiency. With venous insufficiency treatment, wound clean-up and local wound care were initiated, but there was no regression of ulcers and new ulcers emerged both on the left ankle and behind the right leg (Figure 2). A punch biopsy was performed and histopathological findings showed neutrophils and fibrinoid material within the vessel wall near the ulcer. During this process the patient was re-examined, and an ulceration on the right scrotal area was detected; a more elaborate medical history revealed recurring oral aphthae and a previous uveitis attack. These findings were compatible with the International Study Group criteria and a diagnosis of Behçet's disease was made. It was concluded that ulcers not responding to treatment were extragenital ulcers associated with Behçet's disease. Systemic methyl prednisolone and colchicine treatment provided a rapid regression of both the leg and genital ulcerations (Figure 3). Behçet's disease is a systemic vasculitic disease with unknown aetiology. In 1937, Prof. Dr Hulusi Behçet described it as a classical triad consisting of eye inflammation and oral and genital ulcers.1 As well as mucocutaneous involvement, vascular, gastrointestinal, and joint involvement are the other common manifestations of Behçet's disease. The average onset age is between 20 and 40 years. Men and women are equally affected but the disease is more severe in men.2 Although the pathogenesis is unclear, the strongest view is that T-cell mediated activation by an unknown antigenic stimulation is the case.3-5 Diagnostic criteria established by the International Study Group is currently in use for diagnosis. Recurrent oral ulceration is the necessary finding along with two of the following: genital ulceration, eye disease, skin lesions, and a positive pathergy test.6 There are no laboratory tests specific for Behçet's disease. Chronic disease anaemia and leucocytosis may be present. Erythrocyte sedimentation rate and C-reactive protein level elevations in correlation with disease activation may be detected.7 Corticosteroids, colchicine, cyclosporine, azathioprine, and cyclophosphamide are treatment choices individualised according to the involved systems. Extragenital ulcers are rarely seen in Behçet's disease and clinically resemble genital ulcers and heal with scar formation.8 This patient already had a reason for the leg ulcer, venous insufficiency, which is a very common aetiology, but a elaborate follow up and re-evaluation provided the diagnosis of Behçet's disease. Timely diagnosis may prevent life-long morbidities for the patient with Behçet's disease. The authors received no financial support for the research and/or authorship of this article. The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.
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Behçet's disease is a complex disease characterized by remission and activation periods of unknown duration. It has an unpredictable course. Behçet's disease shows a heterogeneous pattern of organ involvement that occurs in recurrent episodes of acute inflammation throughout the course of the disease. Disease activity in Behçet's disease is difficult to define because of its fluctuating course, lack of laboratory tests reflecting overall disease activity, absence of a standardized form to report the severity of Behcet's disease manifestations and also trying to develop new diagnostic criteria. This led to the development of standardized disease activity index. To be useful, a measurement of disease activity must be valid, reliable, and simple enough to use in routine clinical practice. We will try to explain what the situation is in terms of Behçet's disease activity index.
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Systemic vasculitis
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