Description of the condition
Behçet's Syndrome (BS) is a chronic, relapsing, inflammatory vascular disease characterised by ulcers in the mouth and on the genitals, and inflammation in parts of the eye (uveitis) as well as arthritis (swollen, painful, stiff joints), skin problems, and inflammation of the digestive tract, brain, and spinal cord. Onset most commonly occurs in adults, but paediatric cases have been reported. Both genders are affected equally, but the disease runs a more severe course in males (Yazici 2012). The disease course is characterised by exacerbations and remission ending in a total remission in at least 60% of patients at 20 years of follow-up (Kural-Seyahi 2003).
The disease is of unknown origin. There is no evidence of an infectious cause. A correlation between genetic predisposition and triggering extrinsic factors has been suggested, because more than 60% of BS patients are associated with HLA-B 51 (Yazici 1980; Gül 2012; Kose 2012). Some clinical features show distinct geographical differences. The prevalence is high in Turkey (> 1/1000 people). Fewer cases of intestinal disease are reported in the Mediterranean area; eye disease causes considerable morbidity in Turkish patients (Kural-Seyahi 2003; Tugal-Tutkun 2004) but is rarely a severe problem among Italian (Salvarani 2007) or American patients (Calamia 2009). A positive skin pathergy test is less frequent among patients from northern Europe, America or Japan (Hatemi 2012; Yazici 2012).
The diagnostic criteria for BS were defined by the International Study Group (ISG) for Behçet's Disease in 1990, and include the presence of recurrent oral ulceration, with at least 3 episodes over 12 months, in addition to 2 of the following features: recurrent genital ulcers, eye lesions, skin lesions and a positive pathergy test (ISG 1990). An international team (from 27 countries) has recently proposed a revision of the ISG criteria, in which eye lesions, oral ulcers and genital ulcers are each assigned two points, while skin lesions, Central Nervous System (CNS) involvement and vascular manifestations are assigned one point each. The pathergy test, when used, was assigned one point. A patient scoring four or more points is classified as having BS. These new criteria would have higher sensitivity over the ISG criteria while maintaining reasonable specificity (ICBD 2013).
When the disease involves the CNS it is defined as Neuro-Behçet Syndrome (NBS). Sporadic neurological manifestations are frequent (> 20%), often occurring 1 to 10 years after initial symptoms, but in some cases neurological symptoms are the first manifestation of BS (Akman-Demir 1999; Al-Araji 2009). NBS is more frequent in men than women and it usually occurs at between 20 and 40 years of age ( Al-Araji 2009; Dalvi 2012).
There are two main categories of NBS that should be considered separately: parenchymal and non-parenchymal (Serdaroglu 1998). Parenchymal NBS includes the following four syndromes:
- Brainstem involvement that includes ophthalmoparesis, cranial neuropathy, and cerebellar or pyramidal dysfunction.
- Cerebral hemispheric involvement that presents with encephalopathy, hemiparesis, hemisensory loss, seizures, dysphasia, cognitive dysfunction and psychosis.
- Spinal cord involvement that occurs with pyramidal signs in the limbs, sensory level dysfunction, and, commonly, sphincter dysfunction.
- Evidence for cerebral or spinal cord involvement in addition to the brainstem signs and symptoms.
Non-parenchymal NBS occurs as cerebral venous thrombosis or intracranial and extracranial aneurysm (Al-Araji 2009). Patients with non-parenchymal NBS have a significantly better prognosis than those with parenchymal NBS (Siva 2001).
Around a third of NBS patients have single episodes, a third have repeated relapses with remission, and a third undergo a progressive disease course with accrual of multiple functional disability (Akman-Demir 1999; Al-Fahad 1999; Kidd 1999; Siva 2001; Kural-Seyahi 2003). High cellular and/or protein content in the cerebrospinal fluid and parenchymal involvement, especially of the brainstem, are associated with a worse prognosis (Akman-Demir 1999).
Description of the intervention
There is no cure for BS. Treatments focus on relieving the symptoms and preventing worsening or complications.
Treatments for BS include: biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha. Corticosteroids are prescribed for acute exacerbations, to reduce severe joint pain, skin sores, eye disease, or CNS symptoms. Long-term use of corticosteroids in addition to immunosuppressants is also reported. However long-term corticosteroids may cause several side effects such as diabetes, osteoporosis, weight gain, infections, delayed wound healing, persistent heartburn, elevated blood pressure and mental disorders (Mat 2006). Immunosuppressants such as azathioprine, cyclophosphamide, chlorambucil, cyclosporine-A, methotrexate, micophenolate, mitoxantrone, levamisole and tacrolimus are used for patients with BS to reduce inflammation, and prevent exacerbations and complications, but they also cause serious adverse events (Hatemi 2008).
In recent years, there has been considerable interest in evaluating the efficacy of biologics for BS. These compounds have been licensed for use in other conditions, e.g. rheumatoid arthritis, psoriasis, psoriatic arthritis and inﬂammatory bowel disease (Singh 2011). Biologics are a group of medications that suppress the immune system and reduce inﬂammation. Even though suppressing the immune system can increase the risk of infections, it also helps to stabilise an overactive immune system. The following biologics are used off-label for patients with BS: anti-CD20 (rituximab), anti-interleukin (IL)1 (anakinra, canakinumab, gevokizumab, rilonacept), 2 (daclizumab), 6 (tocilizumab), and 17 (secukinumab), and Tumor Necrosis Factor (TNF) inhibitors (adalimumab, etanercept, inﬂiximab). Biologics are administered subcutaneously except for inﬂiximab and rituximab, which are administered as intravenous infusions. Several adverse events such as tuberculosis reactivation with biologics are drug-specific. However, some adverse events such as increased risk of infection are related to a general immunomodulator or immunosuppressive effect and are common to all biologics (Singh 2011).
How the intervention might work
Immunosuppressants are agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others act through activation of T-cells or by inhibiting the activation of helper T-cells, targeting immune mechanisms important in BS pathogenesis (Abbas 2001; Kose 2012).
Biologics are highly specific molecules targeting various immune cells that play a key role in local and systemic inflammation (Singh 2011). Anti-TNF blockers include both soluble receptors that serve as decoy receptors competing with TNF-receptors (etanercept) and monoclonal antibodies targeting the TNF-receptors (adalimumab and infliximab). Rituximab is a monoclonal antibody against CD20, which is found primarily on B-cells. Clinical and laboratory observations suggested an important role of TNF-mediated process in the pathogenesis of BS (Kose 2012). Increased levels of TNF, soluble TNF receptors, and TNF-producing cells were found in the peripheral blood of patients with active disease. Among inﬂammatory cytokine-related genes, TNF blockade reduced expression of IL-1 receptor type 2, interferon γ receptors, IL-6 receptors, and IL-17 receptors (Keino 2011). It was found that inﬂiximab is capable of interfering with gamma delta T cell function in BS characterised by dysregulated cell-mediated immunity (Accardo-Palumbo 2010). Arida analysed published data on 369 patients treated with either adalimumab, etanercept or inﬂiximab, and reported that the majority of patients showed improvement of their mucocutaneous manifestations (Arida 2011). Rituximab was found effective in retinal vasculitis and ocular manifestations in BS (Davatchi 2010). Regeneron and canakinumab are human anti-IL-1β monoclonal antibodies, targeting a cytokine implicated in the pathogenesis of many inﬂammatory diseases. Reports from clinical trials suggest that rilonacept and canakinumab are well tolerated in patients with BS and no serious adverse effects were reported (Dubois 2011).
Why it is important to do this review
A Cochrane review (Saenz 1998) on general management of BS was published in 1998 but it did not consider NBS. A systematic review of all available studies is warranted to evaluate the efficacy and safety of the treatments for NBS.
To assess the efficacy and safety of biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha to improve health condition in patients with Neuro-Behçet Syndrome (NBS).
Criteria for considering studies for this review
Types of studies
Efficacy. We will include randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective controlled cohort studies.
We will classify a trial as a CCT if the author(s) do not state explicitly that the trial was randomised, but randomisation cannot be ruled out. The classification CCT is also applied to quasi-randomised studies, where the method of allocation is known but is not considered strictly random (Higgins 2011).
We will classify as a cohort study a study in which a defined group of people (the cohort) is followed over time, to examine associations between different interventions received and subsequent outcomes. A ‘prospective’ cohort study recruits participants before any intervention and follows them into the future. A ‘retrospective’ cohort study identifies subjects from past records describing the interventions received and follows them from the time of those records (Higgins 2011).
In order to be included, cohort studies have to report on a contemporary control group, and both groups need to be described with sufficient detail to allow assessment of potential 'confounding by indication'. At least baseline characteristics, the treatment regimen and outcome data have to be reported separately for both groups.
Safety. We will include RCTs, CCTs, open-label extension (OLE), cohort and case-control studies, population-based registries, case-series and case-reports.
Types of participants
We will include all patients over 13 years of age with a diagnosis of NBS (as first clinical manifestations of BS or as complication of BS), according to widely accepted diagnostic criteria, such as the International Study Group for Behcet's disease criteria (ISG 1990), or the International Criteria for Behçet's Disease (ICBD 2013), regardless of disease phase (first attack, recurrent or progressive NBS), patient gender and ethnicity, in inpatient or outpatient setting.
Types of interventions
Any treatment compared with any other pharmacological treatment, placebo or no treatment.
- Biologics: anti-CD20 (rituximab), anti-interleukin (IL)1 (anakinra, canakinumab, gevokizumab, rilonacept), 2 (daclizumab), 6 (tocilizumab), and 17 (secukinumab), TNF inhibitors (adalimumab, etanercept, inﬂiximab);
- Immunosuppressants (azathioprine, cyclophosphamide, chlorambucil, cyclosporine-A, methotrexate, micophenolate, mitoxantrone, levamisole, tacrolimus);
Regimens will be included irrespective of their duration and dose, as long as they are within therapeutic range.
Types of outcome measures
Primary efficacy outcomes:
- Induction or maintenance of remission with disease activity considered as a dichotomous outcome, i.e. sustained-remission rate and relapse-free survival (RFS);
- Change of patient-reported outcomes (PROs, e.g. Short Form 36, Behcet disease quality of life (Gilworth 2004), or any other PRO validated measures as reported in primary studies).
- Withdrawals due to serious adverse events (SAEs);
- Proportion of patients with at least one of the following adverse events (AEs):
- infections (pneumonia, fungal and opportunistic infections,tuberculosis reactivation);
- cardiac disorders;
- all cancers, including lymphomas and leukemias; mental disorders;
- any other AE reported in the included studies.
- Time to remission;
- Overall survival (OS);
- Physical and cognitive disability measured with validated instruments, such as the Expanded Disability Status Scale (EDSS).
Disease activity, remission, relapse and disability measures will be included only if they are assessed by validated instruments, as reported in primary studies. SAEs will be defined according to the National Cancer Institute Common Terminology Criteria for AE (CTCAE 2003).
Search methods for identification of studies
No language restrictions will be applied to the search.
The Trials Search Co-ordinator will search the following databases:
- The Cochrane Central Register of Controlled Trials (CENTRAL) (recent issue);
- MEDLINE (PubMed) (1966 to date);
- EMBASE (Embase.com) (1974 to date);
- CINAHL (EbscoHOST) (1981 to date);
- LILACS (Bireme) (1982 to date);
- Clinicaltrials.gov (www.clinicaltrials.gov);
- WHO International Clinical Trials Registry Portal (http://apps.who.int/trialsearch/).
Search terms (Appendix 1) will be adapted to meet the requirements of individual databases as regards to differences in fields.
Searching other resources
- Handsearch reference lists of all relevant retrieved articles, texts and other reviews on the topic;
- Contact authors and researchers active in this field for additional data if necessary.
Data collection and analysis
Selection of studies
Two pairs of review authors (GF and FG; IT and FN) will independently identify each potentially-relevant study obtained from the electronic and manual searches. The first screening will be done by reviewing titles and abstracts. The full-text copies of the selected articles will be evaluated during the second screening. We will record 'excluded studies' and the reasons for exclusion. Disagreements will be discussed and resolved by consensus among review authors. We will use EndNote (https://www.myendnoteweb.com/) to store references.
Data extraction and management
Two review authors (FN, FG) will independently extract data from the included studies using a standardised Excel form. We will contact principal investigators of included studies , if necessary, to request additional data or confirmation of methodological aspects of the study. We will extract the following data from the included studies:
- Study design and year of publication;
- Participants (sample size of any treatment arm, study setting, demographic and clinical characteristics of participants such as age, gender, ethnicity, presence of other BS manifestations);
- Details of the experimental and control interventions (type, duration, schedules and dose);
- Outcomes previously defined (see Types of outcome measures section).
Disagreements will be discussed and resolved by consensus among review authors.
Assessment of risk of bias in included studies
Risk of bias (RoB) will be independently evaluated by two review authors (FN, FG) and reported in an Excel file. Disagreement will be resolved by consensus between the authors. The RoB assessment will be presented in the RevMan table format for each of the included studies.
1) Criteria for assessing risk of bias of RCTs and CCTs.
The risk of bias of RCTs and CCTs will be assessed following the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 (Higgins 2011). Two review authors (FN, FG) will evaluate independently the methodological quality of the studies using the 'Risk of bias' tool under the domains of sequence generation, allocation concealment, blinding of personnel, patients and outcome assessors, incomplete outcome data, selective outcome reporting and other biases.
Using quality at the analysis stage as a mean of interpretation of the results, we will assign RoB categories (Higgins 2011) as low, unclear or high RoB.
RCTs will be classified as being at high RoB if at least one of the following domains is judged to be at high RoB: allocation concealment, blinding of patients and outcome assessors, and incomplete outcome data defined as > 10% to 15% lost to follow-up.
CCTs will be classified as being at high RoB if at least one of the following domains is judged to be at high RoB: selection of patients, blinding of patients and outcome assessors, and incomplete outcome data defined as > 10% to 15% lost to follow-up.
RCTs and CCTs will be classified as being at unclear RoB if they present insufficient information or uncertainty over the potential for bias.
2) Criteria for assessing risk of bias of cohort and case-control studies.
We will assess the risk of bias of these studies in relation to the presence of potential confounders, which could make interpretation of the studies' results difficult. We will evaluate the quality of cohort (prospective and retrospective) and case-control studies using the appropriate Newcastle-Ottawa Scales (NOS) (Appendix 2). The eight items of the NOS related to selection, comparability and outcome/exposure will be customised to the review question and to several predefined potential confounding factors that the researchers have considered and those that have been omitted in the study, the balance between comparator groups (at baseline for cohort studies) with respect to the main prognostic or confounding factors, to identify what researchers did to control for selection bias and other selected biases (e.g. attrition, information, lead-time and null bias). Potential confounding factors considered will be the following: age, gender, ethnicity, clinical phenotypes, disease phase and severity, activity state, treatment phase, and previous treatments.
Cohort and case-control studies will be classified as being at high RoB if at least one of the following domains is judged to be at high RoB: selection, comparability and outcome/exposure. They will be classified as being at unclear RoB if they present insufficient information or uncertainty over the potential for bias.
3) Criteria for assessing quality of safety data.
Safety monitoring will be assessed for each included study using the following criteria:
- AE definition: did the study provide a definition of SAEs and AEs?
- Method of AE assessment: did the researchers actively monitor for SAEs and AEs (low RoB) or did they simply provide spontaneous reporting of SAEs and AEs that arose (high RoB)?
Measures of treatment effect
We will report dichotomous, continuous, and survival data. For dichotomous outcomes, we will calculate the relative risks (RRs) with 95% confidence intervals (CI). For continuous outcomes, means, standard deviations and 95% CI will be reported. Time to event data will be calculated as hazard ratios (HRs) with the corresponding 95% CI.
Unit of analysis issues
The unit of analysis will be individual patients.
Dealing with missing data
For missing data, when possible we will contact the authors of studies to obtain data, otherwise we will perform any appropriate sensitivity analysis with different scenarios (i.e., likely, worst and best case scenarios).
Assessment of heterogeneity
We will assess studies for clinical homogeneity with respect to age, gender, ethnicity, clinical phenotype, disease phase and severity, activity state, type of immunosuppressant and biologic drugs, concomitant drug including steroids use, treatment phase, previous treatments, and length of follow-up. We will assess statistical heterogeneity by the Chi
Assessment of reporting biases
Reporting bias will be examined as a part of the overall RoB assessment. It will be assessed by comparing outcomes stated in protocols to those reported in article. For studies where protocols are not available or cannot be retrieved, reporting biases will be assessed by comparing outcomes listed in the methods section to those in results. If some indications of reporting bias are found, we will contact study authors for clarification. We will prepare a funnel plot (Egger 1997) if at least 10 studies are included in the review, to assess the possibility of publication bias. Asymmetry of the funnel plot found either by inspection or statistical tests will be taken into account in interpreting the overall estimate of treatment effects.
Two review authors (FN, FG) will analyse the data and report them as specified in Chapter 9 (Higgins 2011), and Chapter 13 of the Cochrane Handbook for Systematic Reviews of Interventions (Reeves 2011). For non-randomised studies, if they are judged reasonably resistant to bias and relatively homogeneous in this respect, we will meta-analyse adjusted estimates (i.e., analyses that attempt to control for the predefined confounders), using the inverse-variance weighted average (Reeves 2011). If sufficient numbers of studies are included, analysis will be conducted using Review Manager software (Review Manager 2013) and/or SAS software. If in any case the number and quality of studies is judged to be inadequate for meta-analysis, the evidence provided by the literature will be summarised through qualitative analyses.
We will perform separate meta-analyses according to the study design: RCTs, CCTs, prospective and retrospective cohorts. The main analyses will be of biologics, colchicine, corticosteroids, immunosuppressant and interferon-alpha compared to placebo and to each other.
We will compute pooled estimates using a fixed-effect model. In case of heterogeneity (I
Subgroup analysis and investigation of heterogeneity
We plan to carry out subgroup analyses based on:
- Clinical phenotypes (first attack of NBS, recurrent NBS, progressive NBS, NBS complicating BS);
- Categories of NBS involvement (parenchymal and non-parenchymal);
- Type of immunosuppressant and biologic drug;
- Concomitant drug including steroids use versus no concomitant therapy;
- Treatment phase (therapy for induction or maintenance of remission);
- Previous treatments with immunosuppressants, biologics or interferon-alpha;
- Duration of study (< 12 months versus ≥ 12 months).
We will conduct sensitivity analyses to assess the robustness of our review results by repeating the analyses with the exclusion of studies classified as being at high RoB.
For missing data we will perform any appropriate sensitivity analysis as mentioned above (see Dealing with missing data section).
'Summary of findings' table
We will present the main results of the review in a 'Summary of findings' (SoF) table, as recommended by The Cochrane Collaboration (Schünemann 2011a). The SoF table will include the following major outcomes:
- Induction or maintenance of remission;
- Change of PROs;
- Withdrawals due to SAEs.
The SoF table will include an overall grading of the quality of evidence related to each of the outcomes, using the GRADE approach (Schünemann 2011b).
We thank Peter Tugwell, Richard Wordmald and Carlo Di Pietrantonj for useful comments during the preparation of the manuscript.
Appendix 1. Key Words
Behcet* OR “Triple-Symptom Complex” OR “Triple Symptom Complex”
Filters: Humans; Adolescent: 13-18 years; Adult: 19+ years.
Appendix 2. Newcastle - Ottawa quality assessment scale for cohort and case control studies
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability
1) Representativeness of the exposed cohort
a) truly representative of the average _______________ (describe) in the community *
b) somewhat representative of the average ______________ in the community *
c) selected group of users eg nurses, volunteers
d) no description of the derivation of the cohort
2) Selection of the non exposed cohort
a) drawn from the same community as the exposed cohort *
b) drawn from a different source
c) no description of the derivation of the non exposed cohort
3) Ascertainment of exposure
a) secure record (eg surgical records) *
b) structured interview *
c) written self report
d) no description
4) Demonstration that outcome of interest was not present at start of study
a) yes *
1) Comparability of cohorts on the basis of the design or analysis
a) study controls for _____________ (select the most important factor) *
b) study controls for any additional factor ¯ (This criteria could be modified to indicate specific control for a second important factor.)
1) Assessment of outcome
a) independent blind assessment *
b) record linkage *
c) self report
d) no description
2) Was follow-up long enough for outcomes to occur
a) yes (select an adequate follow up period for outcome of interest) *
3) Adequacy of follow up of cohorts
a) complete follow up - all subjects accounted for *
b) subjects lost to follow up unlikely to introduce bias - small number lost - > ____ % (select an adequate %) follow up, or description provided of those lost) *
c) follow up rate < ____% (select an adequate %) and no description of those lost
d) no statement
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
CASE CONTROL STUDIES
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Exposure categories. A maximum of two stars can be given for Comparability.
1) Is the case definition adequate?
a) yes, with independent validation *
b) yes, eg record linkage or based on self reports
c) no description
2) Representativeness of the cases
a) consecutive or obviously representative series of cases *
b) potential for selection biases or not stated
3) Selection of Controls
a) community controls *
b) hospital controls
c) no description
4) Definition of Controls
a) no history of disease (endpoint) *
b) no description of source
1) Comparability of cases and controls on the basis of the design or analysis
a) study controls for _______________ (Select the most important factor.) *
b) study controls for any additional factor * (This criteria could be modified to indicate specific control for a second important factor.)
1)Ascertainment of exposure
a) secure record (eg surgical records) *
b) structured interview where blind to case/control status *
c) interview not blinded to case/control status
d) written self report or medical record only
e) no description
2) Same method of ascertainment for cases and controls
a) yes *
3) Non-Response rate
a) same rate for both groups *
b) non respondents described
c) rate different and no designation
Contributions of authors
All review authors were involved in all aspects of the protocol.
Declarations of interest
Sources of support
- Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta Milano, Italy.Support the editorial base of "Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group"
- Protocol submitted to the independent research programme of the Italian Medicines Agency (AIFA), Italy.Financially support the reviewers