Recomendaciones SER sobre el tratamiento del síndrome de Behçet refractario / SER recommendations on treatment of refractory Behçet's syndrome

Objetivo: Elaborar recomendaciones multidisciplinares, basadas en la evidencia disponible y el consenso de expertos, para el manejo terapéutico de los pacientes con síndrome de Behçet refractario (difícil de tratar, resistente grave, recidivante grave) al tratamiento convencional. Métodos: Un panel de expertos identificó preguntas clínicas de investigación relevantes para el objetivo del documento. Estas preguntas fueron reformuladas en formato PICO –paciente, intervención, comparación, outcome o desenlace–. A continuación, se realizaron revisiones sistemáticas; la evaluación de la calidad de la evidencia se realizó siguiendo la metodología del grupo internacional de trabajo Grading of Recommendations, Assessment, Development, and Evaluation. Tras esto, el panel multidisciplinar formuló las recomendaciones. Resultados: Se seleccionaron 4 preguntas PICO relativas a la eficacia y seguridad de los tratamientos farmacológicos sistémicos en los pacientes con síndrome de Behçet con manifestaciones clínicas refractarias a terapia convencional, relacionadas con los fenotipos mucocutáneo y/o articular, vascular, neurológico-parenquimatoso y gastrointestinal. Se formularon un total de 7 recomendaciones estructuradas por pregunta, con base en la evidencia encontrada y el consenso de expertos. Conclusiones: El tratamiento de las manifestaciones clínicas más graves del síndrome de Behçet carece de evidencia científica sólida y no existen documentos de recomendaciones específicas para los pacientes con enfermedad refractaria a la terapia convencional. Con el fin de aportar una respuesta a esta necesidad, se presenta el primer documento de recomendaciones de la Sociedad Española de Reumatología específicas para el abordaje terapéutico de estos pacientes, que servirá de ayuda en la toma de decisiones clínica y la reducción de la variabilidad en la atención.(AU)

Objective: To develop multidisciplinary recommendations based on available evidence and expert consensus for the therapeutic management of patients with refractory Behçet's syndrome (difficult to treat, severe resistant, severe relapse) to conventional treatment. Methods: A group of experts identified clinical research questions relevant to the objective of the document. These questions were reformulated in PICO format –patient, intervention, comparison and outcome–. Systematic reviews of the evidence were conducted; the quality of the evidence was evaluated following the methodology of the international working group Grading of Recommendations, Assessment, Development, and Evaluation. After that, the multidisciplinary panel formulated the specific recommendations. Results: Four PICO questions were selected regarding the efficacy and safety of systemic pharmacological treatments in patients with Behçet's syndrome with clinical manifestations refractory to conventional therapy related to mucocutaneous and/or articular, vascular, neurological parenchymal and gastrointestinal phenotypes. A total of 7 recommendations were made, structured by question, based on the identified evidence and expert consensus. Conclusions: The treatment of most severe clinical manifestations of Behçet's syndrome lacks solid scientific evidence and, besides, there are no specific recommendation documents for patients with refractory disease. With the aim of providing a response to this need, here we present the first official recommendations of the Spanish Society of Rheumatology for the management of these patients. They are devised as a tool for assistance in clinical decision making, therapeutic homogenisation and to reduce variability in the care of these patients.(AU)

An immune-related adverse event of Behcet's-like syndrome following pembrolizumab treatment.

BACKGROUND: In recent years, the emergence of immunotherapy has renewed therapeutic modality. Different from traditional anti-tumor therapy, immune-related adverse events of skin, gastrointestinal tract, liver, lung, endocrine glands commonly occurred. At present, only one case of immune-related adverse event of Behcet's-like syndrome following pembrolizumab treatment was reported in USA, and no one is reported in China. CASE PRESENTATION: Here, we report a rare case of Behcet's-like symptom following pembrolizumab treatment. A 43-year-old female was diagnosed as lymph node and bone metastasis of adenocarcinoma with unknown primary lesion, probably being of pulmonary origin. She was treated with pembrolizumab 200 mg every three weeks in combination with chemotherapy for 6 cycles, followed by pembrolizumab monotherapy maintenance. However, she developed Behcet's-like syndrome with oral ulcer, genital uler, phlebitis, and vision loss after 9 cycles of pembrolizumab treatment. She was treated with prednisone 5 mg orally three times a day. Two weeks later, dose of glucocorticoid gaven to the patient gradually decreased with improved symptoms. After a treatment-free withdrawal period, the patient requested to continue pembrolizumab treatment. Unfortunately, the above symptoms recurred on the second day following pembrolizumab treatment, and glucocorticoid was taken once again. The symptoms improved and the condition was under control. CONCLUSIONS: In view of the exponential growth of immunocheckpoint inhibitors (ICIs) in a variety of tumors, we should be alert to related adverse events, especially the rare rheumatic manifestations.

Coexistence of ankylosing spondylitis and Behçet's disease: Successful treatment with upadacitinib.

BACKGROUND: Ankylosing spondylitis (AS) and Behçet's disease (BD) are distinct inflammatory disorders, but their coexistence is a rare clinical entity. This case sheds light on managing this complex scenario with Janus kinase (JAK) inhibitors. CASE PRESENTATION: A 42-year-old woman presented with a decade-long history of lower back pain, nocturnal spinal discomfort, recurrent eye issues, oral and genital ulcers, hearing loss, pus formation in the left eye, and abdominal pain. Multidisciplinary consultations and diagnostic tests confirmed AS (HLA-B27 positivity and sacroiliitis) and BD (HLA-B51). Elevated acute-phase markers were observed. CONCLUSION: This case fulfills diagnostic criteria for both AS and BD, emphasizing their coexistence. Notably, treatment with upadacitinib exhibited promising efficacy, underscoring its potential as a therapeutic option in patients with contraindications for conventional treatments. Our findings illuminate the intricate management of patients presenting with these two diverse systemic conditions and advocate for further exploration of JAK inhibitors in similar cases.

Long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha treatment for patients with Behcet's uveitis: A systematic review and meta-analysis.

AIM: This study aims to evaluate the long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha (anti-TNF-α) therapy for patients with Behcet's uveitis (BU) using meta-analysis. METHODS: We searched the Web of Science and PubMed databases for eligible studies up to December 1, 2022. The quality of each identified study was assessed using the Joanna Briggs Institute's case series literature quality assessment tool. Statistical analysis was conducted using Stata 16.0 software with a random-effects model. RESULTS: Twelve studies comprising 1156 patients with BU were included in our analysis. We found that 85.0% of patients achieved ocular inflammation remission after receiving anti-TNF-α treatment, with a 95% confidence interval (CI) ranging from 78.7% to 90.5%. Additionally, 77.4% (95% CI: 57.5%-92.5%) experienced an improvement in visual acuity (VA). Moreover, the pooled dose reduction of glucocorticoids (GCs) was 11.08 mg (95% CI: -13.34 mg to -8.83 mg). Throughout the follow-up period, the cumulative retention rate of the medication was 67.3% (95% CI: 53.7%-79.6%). Serious adverse events occurred in 5.8% (95% CI: 3.1%-8.9%) of cases, with the three most common types being severe infusion or injection reactions (2.7%; 95% CI: 0.8%-5.4%), tuberculosis (1.3%; 95% CI: 0.0%-3.9%), and bacterial pneumonia (1.3%; 95% CI: 0.1%-3.4%). Subgroup analysis revealed that ocular inflammation remission rates were 89.3% (95% CI: 81.2%-95.5%) for adalimumab treatment and 83.7% (95% CI: 75.3%-90.8%) for infliximab treatment. The drug retention rate after adalimumab therapy was 70.3% (95% CI: 62.0%-78.0%) compared to 66.4% (95% CI: 48.6%-82.2%) for infliximab treatment. Furthermore, the incidence of severe infusion or injection reactions was 2.2% (95% CI: 0.1%-5.8%) following adalimumab treatment and 3.5% (95% CI: 0.7%-7.7%) following infliximab treatment. CONCLUSIONS: Anti-TNF-α therapy represents an effective treatment for BU patients with favorable safety profile and high drug retention rate and a potential advantage of adalimumab over infliximab in terms of ocular inflammation remission, drug retention, and the incidence of severe infusion or injection reactions.

Behçet's syndrome.

Behçet's syndrome is a rare, chronic multisystemic inflammatory disorder also known as the Silk Route disease due to its geographical distribution. Behçet's syndrome is a multifactorial disease and infectious, genetic, epigenetic, and immunological factors contribute to its pathogenesis. Its heterogeneous spectrum of clinical features include mucocutaneous, articular, ocular, vascular, neurological, and gastrointestinal manifestations that can present with a relapsing and remitting course. Differential diagnosis is often hampered by the non-specific clinical presentation and the absence of laboratory biomarkers or pathognomonic histological features. The therapeutic approach is tailored on the basis of patient-specific manifestations and relies on glucocorticoids, colchicine, and traditional and biological immunosuppressants. Despite progress in the knowledge and management of the disease, unmet needs in diagnostics, monitoring, prediction, and treatment personalisation challenge clinical practice, making Behçet's syndrome a complex disorder associated with an increased risk of morbidity.

Characterization and Management of Amicrobial Pustulosis of the Folds, Aseptic Abscess Syndrome, Behçet Disease, Neutrophilic Eccrine Hidradenitis, and Pyostomatitis Vegetans-Pyodermatitis Vegetans.

Neutrophilic dermatoses are a broadly heterogeneous group of inflammatory skin disorders. This article reviews 5 conditions: amicrobial pustulosis of the folds, aseptic abscess syndrome, Behçet disease, neutrophilic eccrine hidradenitis, and pyostomatitis vegetans-pyodermatitis vegetans.The authors include up-to-date information about their epidemiology, pathogenesis, clinicopathologic features, diagnosis, and management.

Neither hepatic steatosis nor fibrosis is associated with clinical outcomes in patients with intestinal Behçet's disease.

BACKGROUND: Behçet's disease (BD) and nonalcoholic fatty liver disease (NAFLD) are chronic inflammatory diseases that share pathogenetic mechanisms. In this study, we investigated whether NAFLD influences the clinical outcomes in patients with intestinal BD. METHODS: Patients with intestinal BD and available hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) scores were recruited between 2005 and 2022. An HSI of ≥30 and FIB-4 of ≥1.45 were used to diagnose hepatic steatosis and significant liver fibrosis, respectively. The primary outcomes were intestinal BD-related hospitalization, surgery, emergency room visits, or the first use of corticosteroids, immunomodulators, or biologic agents for intestinal BD. RESULTS: A total of 780 patients with BD were selected. The prevalence of hepatic steatosis and significant liver fibrosis were 72.3% and 8.8%, respectively. Multivariate analysis showed that younger age, prior smoking history, concomitant skin lesions, higher white blood cell count, and lower serum albumin levels were independently associated with an increased risk of clinical relapse (all P < 0.05), whereas hepatic steatosis and significant liver fibrosis were not (hazard ratio [HR] = 1.164, 95% confidence interval [CI] 0.923-1.468; P = 0.199 for hepatic steatosis; HR = 0.982, 95% CI 0.672-1.436; P = 0.927 for significant liver fibrosis). CONCLUSION: Hepatic steatosis and liver fibrotic burden were not independently associated with clinical outcomes in patients with intestinal BD.

Does anticoagulation in combination with immunosuppressive therapy prevent recurrent thrombosis in Behçet's disease?

Vascular involvement in Behçet's disease (BD) occurs in up to 50% of patients. The main mechanism of thrombosis is inflammation. Thus, immunosuppressants (IS) are the mainstay of therapy, and adding anticoagulation (AC) is controversial. In daily practice, we observed that patients who received AC in combination with IS experienced less recurrent thrombosis and decided to investigate our BD patients retrospectively. We hypothesized that adding AC to immunosuppressive therapy may lower the risk of recurrent thrombosis. Treatment at the time of first or recurrent thrombotic events was recorded. Events under the only IS and IS + AC treatments were compared. There were 40 patients (33 males). The most common types of first vascular events were deep vein thrombosis (77.5%) followed by pulmonary embolism (PE) (52.5%). One patient did not receive any treatment. Among the 39 patients, 32 received glucocorticoid and at least one of the azathioprine, or cyclophosphamide, anti-TNF, 5 received monotherapy with azathioprine, 1 received monotherapy with corticosteroid, and the remaining 1 received monotherapy with cyclophosphamide. In total, 22 patients (55%) experienced 27 recurrent venous thromboembolism (VTE) events. Two (7.4%) events while only on AC, 2 (7.4%) events while on AC + IS, and 15 (55.5%) events occurred while on only IS. Eight (19.6%) patients were not receiving any treatment during relapses. The recurrence rate was statistically significantly lower in the IS + AC treatment group compared to IS alone. In conclusion, IS are the mainstay of treatment for BD, and adding AC may help to lower the recurrence risk of thrombotic events.

Predicting Factors of Long-term Outcome of Gastrointestinal Behçet's Disease: A Chinese Retrospective Study.

PURPOSE: Behçet's disease (BD) is a complex disorder affecting multiple systems and organs, and gastrointestinal BD is poorly understood. We aimed to identify factors influencing the long-term outcomes of patients with gastrointestinal BD. METHODS: Consecutive patients with gastrointestinal BD were analyzed retrospectively. Data on the following clinical characteristics were collected: sex, age at diagnosis, symptoms, endoscopic findings, medical treatments, and surgery. Mucosal healing and surgical rates at 1, 2, and 5 years were evaluated. Log-rank test and Cox proportional hazards regression models were used to evaluate the factors affecting long-term outcomes. FINDINGS: Baseline data of 175 patients with gastrointestinal BD were included. The mean (SD) age at diagnosis was 38.3 (12.9) years. The typical clinical symptoms were oral ulcer (72.6%), abdominal pain (71.4%), and weight loss (41.1%). The most commonly involved location was the ileocecum; isolated oval ulcer was the most common ulcer type. Seventeen patients (9.7%) underwent 18 surgeries after inclusion. The cumulative surgical rates were 8.6% (n/N = 15/175), 8.6% (n/N = 15/175), and 9.1% (n/N = 16/175) in 1, 2, and 5 years, respectively. Data from 101 patients who underwent at least 2 endoscopies were included in the analysis for mucosal healing. Kaplan-Meier curve showed that the cumulative mucosal healing rates at 1, 2, and 5 years were 34.7% (n/N = 35/101), 41.6% (n/N = 42/101), and 61.4% (n/N = 62/101), respectively. We compared cumulative mucosal healing rates between 4 treatment groups, including 5-aminosalicylic acid (3% [n/N = 3/101]), mono-immunosuppressant (31.7% [n/N = 32/101]), combined therapy (36.6% [n/N = 37/101]), and escalation therapy (28.7% [n/N = 29/101]), and found that mono-immunosuppressant achieved earlier mucosal healing than combined therapy (P = 0.0008) and escalation therapy (P = 0.0008). The univariate analysis showed that moderate to severe disease activity (P = 0.013, P = 0.004), diameter of the maximal ulcer >4 cm (P = 0.002), and nonsimple esophageal involvement (P < 0.001) were risk factors, and number of ulcers between 2 and 5 was the protective factor of mucosal healing (P = 0.001). Multivariate regression analysis indicated that nonsimple esophageal involvement (P < 0.001) and the maximal ulcer >4 cm (P = 0.041) were independent risk factors of mucosal healing. IMPLICATIONS: Most patients with gastrointestinal BD need long-term treatment to achieve mucosal healing. The location and size of ulcers have a significant impact on the mucosal healing of gastrointestinal BD.

Efficacy of golimumab in patients with refractory non-infectious panuveitis.

This study investigated the efficacy of golimumab in the management of refractory non-infectious panuveitis. Nineteen patients (38 eyes; mean age, 31 years) were retrospectively reviewed between June 2016 and June 2022. All patients had bilateral eye involvement and Behçet's disease was the most common diagnosis (57.9%). Compared to the period before golimumab treatment, the rate of uveitis relapses after golimumab treatment significantly decreased from 1.73 to 0.62 events per person-years (incidence ratio 0.33, 95% confidence interval 0.19-0.57, P < 0.001). After golimumab therapy, 12 patients (63.2%) were able to reduce the number or dosage of immunosuppressive drugs, and the median dosage of systemic corticosteroids was reduced from 15.0 to 7.5 mg/d (P = 0.013) compared to baseline. The median logMAR visual acuity improved from 0.9 at baseline to 0.6 at the last visit (P = 0.006). Golimumab demonstrated efficacy against refractory non-infectious panuveitis in terms of a corticosteroid-sparing effect and reduced the rate of uveitis relapses to approximately one-third.

Hypertension as a prominent manifestation secondary to renal artery lesions in pediatric Behcet's disease.

OBJECTIVE: Hypertension caused by vascular Behcet's disease (BD) is an important prognostic factor of paediatric BD. However, much less is known about its clinical features. The objective of this study was to investigate the clinical characteristics of paediatric vascular BD complicated by hypertension. METHODS: A retrospective study was carried out in paediatric BD patients complicated by hypertension treated in the Children's Hospital Capital Institute of Paediatrics from Jan 2009 to Dec 2022. RESULTS: Of 65 BD patients, 6 (9.2%) were complicated by hypertension, 5 patients were female, and the median ages of onset and diagnosis were 9.8 years and 11.3 years, respectively. Three patients were found to have cardiac involvement and hypertensive retinopathy secondary to hypertension. Five of the 6 patients with hypertension had right renal artery involvement, and all of them were treated with glucocorticoids and immunosuppressants. Four patients were treated with biological agents. One patient with severe renal artery stenosis underwent unsuccessful vascular interventional therapy. After 3-6 years of follow-up, five patients were found to have renal atrophy, and one patient was at stable condition. CONCLUSION: Hypertension in paediatric BD is mainly caused by renal artery involvement. Early recognition and treatment of vascular involvement in BD is important to prevent poor prognosis.

Trends in health care of patients with vasculitides, including giant cell arteritis, Takayasu arteritis, ANCA-associated vasculitis and Behçet's disease: cross-sectional data of the German National Database 2007-2021.

The aim of this study is to present the current care situation of patients with giant cell arteritis (GCA), Takayasu arteritis (TAK), ANCA-associated vasculitis (AAV) and Behçet's disease (BD). Trends over the last 15 years will reflect improvements and remaining deficits in the management of vasculitides. Consecutive cross-sectional data from patients with vasculitides from the German National Database (NDB) of the Collaborative Arthritis Centres between 2007 and 2021 were included. Medication, physician- and patient-reported outcomes on disease activity and disease burden, inpatient stays and occupational participation are compared for different vasculitis entities and over time. Employment rates were compared to German population rates. Between 502 and 854 vasculitis patients were annually documented. GCA and AAV were the most common vasculitides. Median disease duration ranged from 2 to 16 years. Over the years, glucocorticoids decreased in proportion and dose, most markedly in GCA and TAK, while biologic therapies increased up to 27%. Physicians rated disease activity as low for the vast majority of patients, while patients-reported moderate outcomes in many dimensions. PROs remained largely unchanged. The proportion of employed patients (< 65 years) increased from 47 to 57%. In recent years, biologics are increasingly used in patients with vasculitides, while glucocorticoids decreased significantly. PRO's have not improved. Work participation increased but remains lower than that in the German population.

Gastrointestinal Behçet's disease: Manifestations, diagnosis, and management.

Behçet's disease (BD) is a rare, inflammatory vascular disorder with recurrent oral and genital aphthous ulcers, along with ocular and cutaneous manifestations. Gastrointestinal (GI) BD may involve any portion of the GI tract. However, it is commonly described in the terminal ileum, followed by the ileocecal region. Diagnosis is challenging given lack of pathognomonic tests; therefore, it is based on clinical criteria. Management of intestinal BD includes different classes of medications including corticosteroids, 5-aminosalicylic acid, immunomodulators, and anti-tumor necrosis factor alpha monoclonal antibody agents. In this review, we aim to focus on intestinal BD and provide details of clinical manifestations, diagnosis and therapeutic options of intestinal BD from gastroenterology viewpoint.

[Diagnostic modalities of a Behçet uveitis]. / Comment j'explore une uvéite de Behçet.

Behçet disease is a chronic multisystemic inflammatory condition. The ocular disease mainly manifests as a bilateral, non-granulomatous, posterior uveitis or panuveitis, associated with occlusive retinal vasculitis. Uveitis is frequent in Behçet disease, it may be severe, and visually threatening. Early diagnosis and aggressive treatment are mandatory to preserve visual function. Therefore, the goal of this review is to describe the new diagnosis tools and therapeutic guidelines allowing for a significant improvement of the visual prognosis.

La maladie de Behçet est une pathologie inflammatoire chronique multisystémique. L'atteinte oculaire se caractérise le plus souvent par une panuvéite ou uvéite postérieure bilatérale récidivante, non granulomateuse, associée à une vascularite rétinienne occlusive. L'uvéite associée à la maladie de Behçet est fréquente, sévère et potentiellement cécitante en l'absence d'un diagnostic précoce et d'un traitement adapté. L'objectif de cette revue est de décrire les outils diagnostiques et thérapeutiques ayant permis une amélioration significative du pronostic visuel.

Disease and Treatment-Specific Complications of Behçet Syndrome.

PURPOSE OF REVIEW: We aimed to highlight disease-related and treatment-related complications of Behçet syndrome (BS) based on previous and recent studies and our own experience. RECENT FINDINGS: The Behçet's Disease Overall Damage Index is a newly developed instrument to assess damage in BS. Validation studies showed that damage is already present in some patients at diagnosis and continues to progress during the follow-up, mainly related to treatment complications. Nervous system and eye involvement are important causes of long-term disability. Cyclophosphamide seems to be associated with infertility and an increased risk of malignancies among BS patients, prompting the consideration of shortening the treatment duration. Flares in mucocutaneous manifestations have been reported with tocilizumab, and de novo BS manifestations with secukinumab therapy. Earlier diagnosis and treatment are essential to prevent disease-related damage in BS. Treatment-related complications seem to be the leading cause of damage during the disease course.

Neurologic manifestations of Behçet disease: rheumatology experience.

OBJECTIVE: Neurologic involvement in Behçet disease (BD) is a rare manifestation. Herein, we aimed to evaluate the clinical features and treatment choices of neuro-Behçet (NB) patients. METHODS: There were records of 800 BD patients between 1998 and 2021. Fifty-five of the BD patients had NB and the files of these patients were retrospectively evaluated. Patients were grouped into three subgroups: 22 (40%) had non-parenchymal, 25 (45%) had parenchymal, and 8 (15%) had both parenchymal and non-parenchymal (mixed) involvement. RESULTS: Of the 55 patients, 32 were male. Twenty-six of the NB patients were diagnosed with BD simultaneously. The most common complaint was headache (n = 24, 44%). The most affected site was periventricular white matter (n = 21, 38%). All patients had received corticosteroids. Azathioprine (AZA; n = 39, 71%) was the most common immunosuppressive agent after corticosteroids, followed by cyclophosphamide (n = 16, 29%). CONCLUSION: Neurologic involvement is a rare complication of BD but is related to increased mortality and morbidity. Neurologic manifestations may be the initial symptom of BD, thus leading to diagnosis. Both neurology and rheumatology specialists should be aware of this rare condition.

Effect of Infliximab on Chronic Progressive Neuro-Behçet's Disease: Influence of the Timing of Introduction on the Patient Outcome.

Objectives Chronic progressive neuro-Behcet's disease (CPNB) is characterized by progressive deterioration leading to disability. Methotrexate (MTX) has been shown to have beneficial effects on CPNB. However, while infliximab has been found to be effective for patients with inadequate responses to MTX, the appropriate timing for the introduction of infliximab remains unclear. We explored the effects of intervals before the introduction of infliximab on the functional outcome. Methods A retrospective analysis was performed for patients with CPNB who received infliximab and were followed up until October 2015. Functional disability was rated by the Steinbrocker functional classification as used in rheumatoid arthritis. Correlations between the outcomes and intervals before the introduction of infliximab were then analyzed by Spearman's rank correlation test. Patients Eleven patients with CPNB [8 men, 3 women, age 35.2±9.3 years old (mean±standard deviation)] who met the international classification criteria for Behcet's disease were included. Results All 11 patients had received MTX prior to infliximab. The intervals from the onset to the introduction of infliximab and the follow-up periods were 26.6±35.1 months and 65.2±43.6 months [mean±standard deviation], respectively. Among the 11 patients, 2 still showed progression after the introduction of infliximab. The functional disability grades after infliximab treatment were significantly correlated with the intervals from the onset of CPNB to the introduction of infliximab (r=0.6177, p=0.0476). Conclusion The results indicate that the delayed introduction of infliximab leads to irreversible functional disability in CPNB. Thus, it is recommended that infliximab be administered as soon as possible for CPNB patients with inadequate responses to MTX.