Rheumatology, 2025, 64, 74–90

[Link] Rheumatology
Advance access publication 10 September 2024
BSR Guidelines

Guidelines
British Association of Dermatologists and British Society
for Rheumatology living guideline for managing people
with Behçets 2024

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Ruth Murphy1,�,‡, Robert J. Moots2,3,‡, Paul Brogan4, Aykut F. Çelik5, Mark Clement-Jones6,
Ian Coulson7, Adam P. Croft 8, Suzanne Crozier9, Laura Forrest10, Jonathan Harrold11, Steve Higgins12,
Ali S.M. Jawad12, Seema Kalra13, Sidra S. Khan14, Hilary McKee15, Clare E. Pain 16, Harry Petrushkin17,
Ana Poveda-Gallego8, Jane Setterfield18, Poonam Sharma19, Richard West10, Christina Wlodek20,
Maria Hashme21, Lina Manounah21, M. Firouz Mohd Mustapa21, Alina M. Constantin21;
on behalf of the British Association of Dermatologists’ Clinical Standards Unit and the British Society
for Rheumatology
1
Sheffield University Teaching Hospitals NHS Foundation Trust, Sheffield, UK
2
Faculty of Health, Care and Medicine, Edge Hill University, Ormskirk, UK
3
Liverpool University Hospitals NHS Foundation Trust, Aintree University Hospital, Liverpool, UK
4
University College London, Great Ormond Street Institute of Child Health, London, UK
5
Istanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty Hospital, Fatih/Istanbul, Turkey
6
Liverpool Women’s NHS Foundation Trust, Liverpool, UK
7
East Lancashire Hospitals NHS Trust, Burnley, UK
8
University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
9
Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
10
Patient/carer representative
11
Black Country Healthcare NHS Foundation Trust, Wolverhampton, UK
12
Barts Health NHS Trust, London, UK
13
University Hospitals of North Midlands, Staffordshire, UK
14
Withington Community Hospital, Manchester University NHS Foundation Trust, Manchester, UK
15
Northern Health and Social Care Trust, Antrim, Northern Ireland, UK
16
Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
17
Moorfields Eye Hospital NHS Foundation Trust, London, UK
18
King’s College London, London, UK
19
North West Anglia NHS Foundation Trust, Peterborough, UK
20
Saint James Hospital, Sliema, Malta
21
British Association of Dermatologists, Willan House, London, UK
‡
RM and RJM share first authorship.
Produced in 2024 by the British Association of Dermatologists

NICE has renewed accreditation of the process used by the British Association of Dermatologists to produce clinical guidelines. The renewed accreditation
is valid until 31 May 2026 and applies to guidance produced using the processes described in the updated guidance for writing a British Association of
Dermatologists clinical guideline – the adoption of the GRADE methodology 2016. The original accreditation term began on 12 May 2010. More information on
accreditation can be viewed at [Link]/accreditation.
�Correspondence: Ruth Murphy, Sheffield University Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Email: guidelines@[Link]

This is a living guideline prepared for the British Association the British Society for Rheumatology (BSR), including the
of Dermatologists (BAD) Clinical Standards Unit, which Guidelines Steering Group. Members of the BAD’s Clinical
includes the Therapy & Guidelines Subcommittee; and for Standards Unit who have been involved are S.L. Chua (Chair,

Received: 8 August 2024. Accepted: 8 August 2024

This article has been co-published with permission in Rheumatology and British Journal of Dermatology © the British Society for Rheumatology and British
Association of Dermatologists 2024.
All rights reserved. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used
when citing this article.
BAD and BSR living guideline for Behçets 2024 75

Therapy & Guidelines Subcommittee), H. Frow, M. Hashme measures of importance to people with Behçets, ranked
(Information Scientist), L.S. Exton (Senior Guideline according to the GRADE methodology4 (see Section 2.1; and
Research Fellow), M.C. Ezejimofor (Guideline Research Appendix A in the Supporting Information).
Fellow), A.M. Constantin (Guideline Research Fellow) and A systematic literature search of the PubMed, MEDLINE,
M.F. Mohd Mustapa (Director of Clinical Standards). Embase and Cochrane databases was conducted by the tech­
Members of the BSR’s Guidelines Steering Group who have nical team to identify key articles on Behçets up to 25 August
been involved are I. Giles (Chair, Guidelines Steering Group), 2023. The search terms and strategies are detailed in
E. Roddy (Vice Chair, Guidelines Steering Group), C. Appendix M (see Supporting Information). Additional refer­
Cotton, A. Davidson, C. Jones, C. Joyce, A. Kuttikat, D. ences relevant to the topic were also isolated from citations in
Mewar, A. Mootoo and E. Williams. the reviewed literature. Data extraction and critical appraisal,
data synthesis, evidence summaries, lists of excluded studies
and the PRISMA flow diagram were prepared by the techni­
1.0 Purpose and scope cal team. The overall certainty of evidence from the studies
The overall objective of the current iteration of this living

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included in the quantitative review was graded according to
guideline is to provide up-to-date, evidence-based recommen­ the GRADE system (high, moderate, low or very
dations for the management of Behçets disease/syndrome low certainty).
(henceforth termed ‘Behçets’ for simplicity, and as approved In making these recommendations, all GDG members have
by the patient support group) in adults, children and young evaluated the entire dataset obtained from the living system­
people. The document aims to: atic review of the literature pertaining to the clinical question
of interest (Section 2.1).
� offer an appraisal of all relevant literature up to 25 The recommendations were made in discussion with the
August 2023 focusing on any key developments entire GDG, including people with lived experience of
� address important, practical clinical questions relating to Behçets, considering all factors that would affect the strength
the primary guideline objective of the evidence, according to the GRADE approach (i.e. bal­
� provide guideline recommendations and appropriate re­ ance between desirable and undesirable effects, quality of evi­
search recommendations. dence, patient values and preferences, and resource
allocation). All GDG members contributed towards drafting
The guideline is presented as a detailed review with and/or reviewing the narratives and appendices in the
highlighted recommendations for practical use in all appro­ Supporting Information. When insufficient evidence from the
priate community and hospital settings (see Section 3.0), in literature was available, informal consensus was reached
addition to a patient information leaflet (PIL; available on based on the expert opinion of the GDG.
the BAD website: [Link]). The Supporting Information includes summaries of the
findings with forest plots (Appendix B), tables Linking the
Evidence To the Recommendations (LETR) (Appendix C),
2.0 Methodology GRADE evidence profiles indicating the certainty of evidence
This guideline has been developed using the BAD’s recom­ (Appendix D), summaries of the included systematic reviews
mended methodology.1 Further information can be found in (Appendix E), summaries of the comparative studies included
Appendix L (see Supporting Information) with reference to in the quantitative and qualitative syntheses (Appendix F),
the AGREE II instrument ([Link])2 and narrative findings from noncomparative studies (Appendix
GRADE3 (Appendix L). While the recommendations were G), PRISMA flow diagram (Appendix H), critical appraisals
developed for anticipated implementation in the UK National of the included systematic reviews using AMSTAR-2
Health Service (NHS), they could equally be adapted in other (Appendix I), risk-of-bias analyses (Appendix J) and lists of
healthcare systems, internationally, acknowledging different excluded studies (Appendix K).
countries’ health systems, including their priorities, legisla­ The strength of recommendation is expressed by the word­
tion, drug availabilities, funding and policies. ing and symbols shown in Table 1.
The Guideline Development Group (GDG) consisted of Applicability of the recommendations to clinical practice is
four consultant dermatologists (RM, IC, JS, CW), five con­ outlined in Sections 3.2, 4.0, 5.7, 5.8 and 5.10. A ‘patient val­
sultant rheumatologists (RJM, ASMJ, PB, CEP, PS), among ues and preferences’ section and further discussion of the in­
whom two were paediatric consultant rheumatologists (PB, cluded evidence, treatment options, practical and economic
CEP), one consultant gastroenterologist (AFC), one consul­ considerations and service provision is also featured in the
tant ophthalmologist (HP), two consultants in oral medicine LETR narrative (Appendix C).
(JS, APG), one consultant neurologist (SK), one consultant in
obstetrics and gynaecology (MCJ), three clinical psycholo­ 2.1 Clinical questions and outcomes
gists (SC, JH, SH), one dermatology registrar (SSK), one The GDG established a systematic review question pertinent
rheumatology registrar (APC), one pharmacist (HM), two to the scope of the guideline. See Appendix A for the full liv­
people with lived experience of Behçets (LF, RW) and a tech­ ing systematic review protocol.
nical team, which consisted of one information scientist The GDG also established a set of outcome measures of im­
(MH), two guideline research fellows (LM, AMC) and a proj­ portance to people with Behçets, which were agreed by peo­
ect manager (MFMM) providing methodological and techni­ ple with lived experience of Behçets and ranked according to
cal support. the GRADE methodology.4 Outcomes ranked 7, 8 or 9 are
The GDG established one systematic review question perti­ critical for decision making and those ranked 6 are impor­
nent to the scope of the guideline and a set of outcome tant, but not critical for decision making.
76 Ruth Murphy et al.

Table 1. Strength of recommendation

Strength Wording Symbol Definition

Strong recommendation ‘Offer’ (or similar, e.g. "" Benefits of the intervention outweigh the risks; most patients would
for the use of an ‘use’, ‘provide’, ‘take’, choose the intervention while only a small proportion would not; for
intervention ‘investigate’ etc.) clinicians, most of their patients would receive the intervention; for
policymakers, it would be a useful performance indicator
Weak recommendation ‘Consider’ " Risks and benefits of the intervention are finely balanced; most patients
for the use of an would choose the intervention, but many would not; clinicians would
intervention need to consider the pros and cons for the patient in the context of the
evidence; for policymakers it would be a poor performance indicator
where variability in practice is expected
No recommendation Θ Insufficient evidence to support any recommendation
Strong recommendation ‘Do not offer’ ## Risks of the intervention outweigh the benefits; most patients would not
against the use of an choose the intervention while only a small proportion would; for clini­

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intervention cians, most of their patients would not receive the intervention

Systematic review question: In people with Behçets, what is of recommendation ratings see Section 2.0. The GDG is
the clinical effectiveness and safety of interventions compared aware of the lack of high-certainty evidence for some of these
with each other or placebo? recommendations; therefore strong recommendations with
Outcomes: an asterisk (�) are based on available evidence, as well as con­
Critical sensus within the GDG and specialist experience. Good prac­
� Time to disease flares/frequency of flaresa (9) tice point (GPP) recommendations are derived from informal
� Quality of life, for example Behcet’s Disease Quality of expert consensus.
Life (BD-QoL), Short Form Health Survey (SF-36),
3.1 General considerations
Dermatology Life Quality Index (DLQI) or Children’s
Dermatology Life Quality Index (CDLQI), Chronic Oral The GDG set out to provide an up-to-date, holistic and
Mucosal Disease Questionnaire (COMDQ) (9) evidence-based approach to optimize the management of peo­
� Pain (9) ple with Behçets, factoring in patient values and preferences.
� Improvement in disease activity (9) Behçets can present in different ways, depending on which
� Disease activity scores (e.g. Behçet’s Disease Current organs are involved. This means that multispecialty input is
Activity Scale score) (9) needed to optimize disease management. With the advent of
� Induced remissiona (8) targeted therapies, there are currently 62 clinical trials regis­
� Serious adverse effects (grades 3–4), including treatment tered on clinicaltrials.gov5 for the treatment of this condition
failure (e.g. secondary) (8) (Appendix O; see Supporting Information).
� Improvement in psychological functioning, for example Although several classes of drugs can be used to treat vari­
mood, Patient Health Questionnaire-9 (PHQ-9), Hospital ous Behçets-associated symptoms, the majority of these medi­
Anxiety and Depression Scale (HADS) (8) cations are not licensed for this condition. Furthermore, some
� Laboratory changes in white cell count (WCC), C-reactive recommended interventions may not be widely available in
protein (CRP) and erythrocyte sedimentation rate the UK.
(ESR) (7) 3.2 Recommendations
All recommendations that employ the term people refer to
Important adults, children and young people. The terms ‘female’, ‘male’,
� Mild adverse effects (grades 1–2) (6) ‘women’ and ‘men’ used throughout this living guideline refer
to the sex assigned at birth.
a
Overall and/or organ-specific assessment:
Approaches to therapy
� skin and mucocutaneous (e.g. number of episodes of ery­ While Behçets is a rare disorder, in the UK the mucocutane­
thema nodosum, number of lesions/ulcers) ous variant is the most common presentation. In recent years,
� vascular (e.g. occurrence of deep-vein thrombosis) the development of targeted monoclonal therapies has led to
� ocular (e.g. visual acuity, number of uveitis attacks, ocu­ therapeutic advances in disease management. Affected indi­
lar lesions) viduals usually report recurrent aphthous-type ulcers of vary­
� gastrointestinal (e.g. ileocecal ulcer) ing severity, in the oral cavity and anogenital region, in
� nervous system (e.g. central nervous system lesions). conjunction with a range of often nonspecific inflammatory
skin lesions such as erythema nodosum, pyoderma gangreno­
sum and acneiform lesions. These individuals may also de­
scribe lethargy and arthralgia (see R14–R31).
3.0 Summary of recommendations When considering therapeutic escalation, always take into
The following recommendations and ratings were agreed account the overall disease control and any relevant associ­
upon unanimously by all members of the GDG, including ated disease affecting other organs that might require sys­
people with lived experience of Behçets. For further informa­ temic therapy to prevent organ damage or reduce disease
tion on the wording used for recommendations and strength flares and improve quality of life (QoL). Given the extent of
BAD and BSR living guideline for Behçets 2024 77

organs that may be affected in Behçets, multiple medical spe­ their condition is unlikely to affect the baby. Most people
cialties are needed to optimize patient care. Where possible, have an improvement of their symptoms during pregnancy,
this should include awareness of the psychological impact of while only 15–30% will experience a flare,6 notably oral or
a rare disorder that is difficult to diagnose and can be chal­ genital ulceration. Such ulceration can be treated symptomat­
lenging to manage effectively (see R1–R13 and R84–R87). ically and, usually, topical therapies will suffice. Oral or par­
Corticosteroids (CS) are of benefit in Behçets to provide enteral CS are also safe.
disease control during flares or to test whether the affected Before conception, women with Behçets can have their
individual is likely to benefit from longer-term immunosup­ medication reviewed. The majority of medications that are
pression. CS may be given orally or parenterally according to commonly used to treat Behçets are safe in pregnancy; how­
disease severity and patient factors. CS may be used as initial ever, it is important that those few women treated with either
adjunctive therapy with the initiation of an immunosuppres­ thalidomide or mycophenolate mofetil7 must cease treatment
sant (e.g. azathioprine) until therapeutic efficiency is reached. prior to actively trying to conceive and should continue with
Given the extensive adverse-effect profile of long-term CS, it adequate contraception during this time.
is advisable to use the lowest dose of CS required, for the

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The cutaneous condition, pathergy, is more common in
shortest time. A frequent or prolonged requirement for CS individuals with Behçets. This condition is an exaggerated re­
indicates the need to consider drugs with other mechanisms sponse to skin injury. Following vaginal delivery, vulval and
of action, such as small-molecule immunosuppressants or bi­ perineal trauma (although often minor) is common. Some
ologic therapies (see R14–R17, R24–26, R32, R33, R40, women concerned about pathergy may opt for elective cae­
R43, R44, R60–R62, R64, R67, R68, R71, R73–R75, R78). sarean section. These patients should be aware that pathergy
The treatment strategy for gastrointestinal (GI) Behçets can also develop within a caesarean-section wound. This can
should be based on the reduction of GI symptoms by healing usually be managed by use of CS, topically or systemically.
the ulcers, both macroscopically and microscopically, to re­ Postdelivery, women should be assured that the medica­
duce their associated complications. tions that they have taken during pregnancy are generally
Surgery for GI involvement may be needed in treatment- safe during breastfeeding too (see R79–R83).
resistant disease when there is a risk of bleeding and or perfo­ Behçets is very rare in children and young people up to the
ration; a temporary stoma may be required to control compli­ age of 16 years. A UK study showed the 2-year-period preva­
cations. To avoid repeated anastomotic recurrences and/or lence estimate to be 4.2 per million [95% confidence interval
complications some patients may need long-term or lifelong, (CI) 3.2–5.4], and the incidence was 0.96 per million person-
permanent stoma formation (see R32–R42).
years (95% CI 0.66–1.41). Mucocutaneous disease was the
Manifestation of ocular disease is often the driving factor
most common variant. Other organ involvement was less
that leads patients to seek medical attention. Ocular disease
common than in adults (ocular 17.9%, neurological 3.6%
in Behçets is sight threatening and, if left untreated, results in
and vascular 5.4%). Over 83% of children and young people
complete loss of vision within 4 years in up to 90% of
had three or more specialists involved in their care.8
patients. Systemic or intravitreal CS are effective in managing
sight-threatening disease. Longer-term therapy with disease-
General management
modifying antirheumatic drugs and biologics would normally
be considered for this group of patients (see R43–R49). R1 (GPP) If Behçets is suspected, convene a multidisciplinary
A disease flare in Behçets is personalized to the affected in­ team (MDT) involving core specialties and any other relevant
dividual, with a recognizable set of symptoms. The serologi­ specialties (i.e. dermatology, oral medicine, ophthalmology,
cal markers for inflammation are often not raised. However, gastroenterology, rheumatology and clinical psychology,
severe flares can lead to endothelial vascular involvement, with neurology and vascular surgery input, where appropri­
which increases the risk of arterial aneurysm and venous ate) when managing people with Behçets of all ages. Children
thrombosis, often present together. Therefore, it is important and young people with Behçets should be managed within an
to manage these acute flares by inducing remission with fast- MDT appropriate to their age and development. Referral of
acting therapies such as high-dose parenteral CS and/or patients to a national Behçets centre may be indicated to opti­
infliximab. In those with established thromboembolic dis­ mize diagnosis and treatment.
ease, anticoagulation is only recommended in addition to im­ R2 (GPP) Consider the criteria of the 1990 International
munosuppressive therapy after arterial involvement and Study Group (ISG) or the International Criteria for Behcet’s
aneurysm formation have been excluded by appropriate im­ Disease (ICBD) when diagnosing people with sus­
aging, as anticoagulation use in this group is otherwise con­ pected Behçets.
traindicated (see R50–R70 and R71–R78). R3 (GPP) Ensure that the assessment of overall disease ac­
Behçets is a condition that is often diagnosed and treated in tivity considers both, the Physician’s Global Assessment and
women and those of childbearing age. Ideally, potentially patient-reported outcomes, or a Behçets-specific disease activ­
childbearing patients with the condition should be managed ity tool.
in a multidisciplinary setting, including physicians with an in­ R4 (GPP) Assess, within the multidisciplinary team, at each
terest or expertise in rheumatological conditions and obstetri­ visit, the extent of organ involvement and target therapy ac­
cians with an interest, training or expertise in perinatal cordingly, to avoid permanent organ damage.
medicine. When considering hormonal contraception, it R5 (GPP) Provide people with Behçets, at the time of diag­
should be noted that some people with Behçets have a poten­ nosis, with a patient information leaflet (e.g. from the British
tial increased risk of thrombosis. Association of Dermatologists: [Link]/
Women of childbearing age with Behçets should be advised a-z-conditions-treatments) and engage people with Behçets,
to seek pre-conception counselling from the multidisciplinary throughout their treatment pathway, in conversation about
team. They can be advised to start taking folic acid and that their condition to ensure shared decision making.
78 Ruth Murphy et al.

R6 (GPP) Assess the disease impact, at diagnosis and at R20 (") Consider apremilast, where available, as a fourth-
each follow-up visit, by employing a quality-of-life assess­ line option to treat mucocutaneous lesions in adults with
ment tool. Behçets in whom conventional systemic therapies have failed.
R7 (GPP) Consider an antimetabolite (e.g. methotrexate or R21 (") Consider secukinumab as a fourth-line option to
azathioprine) with anti-tumour necrosis factor therapy in treat mucocutaneous lesions in the absence of gastrointestinal
people with Behçets to prevent or delay production of anti­ and/or ocular involvement in adults and children aged ≥ 6
drug antibodies. years with Behçets who have poorly controlled symptoms
R8 (##) Do not offer� thalidomide to people with Behçets, and/or with other organ involvement refractory to conven­
unless there are exceptional circumstances, due to its adverse tional systemic therapies and in whom anti-tumour necrosis
effects profile (e.g. teratogenicity and neurotoxicity). factor therapy has failed or is contraindicated.
R9 (GPP) Advise people with Behçets who present with se­ R22 (") Consider dapsone as a treatment option in people
vere oral aphthous-like ulcers on simple oral hygiene meas­ with Behçets.
ures, having regular dental appointments and the use of
topical antiseptics (e.g. chlorhexidine mouthwash) and the

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Θ There is insufficient evidence to recommend topical
avoidance of irritants such as sodium lauryl sulfate in tooth­ calcineurin inhibitors for people with Behçets.
paste or any identified food. Θ There is insufficient evidence to recommend colchi-
R10 (GPP) Be aware that a pathergic response may be trig­ cine to treat folliculitis in adults with Behçets.
gered in some people following vaccination and/or surgery. Θ There is insufficient evidence to recommend sucral-
R11 (GPP) Be aware that paradoxical Behçets has been fate to treat genital ulcers in people with Behçets.
reported in association with interleukin-17 inhibitors.
R12 (GPP) The transition from children’s to adults’ serv­
ices should be in line with National Institute for Health and Arthritis/arthralgia
Care Excellence guideline NG43.9 Transition should be de­ R23 ("") Offer colchicine as a first-line option to treat arthri­
velopmentally appropriate and follow a person-centred ap­ tis/arthralgia in people with Behçets if there is no other seri­
proach. Point of transfer to adult care should take place at a ous organ involvement. To avoid gastrointestinal side-effects,
time of relative stability for the young person and not be increase the colchicine dose gradually, in line with the manu­
based on a rigid age threshold. facturers’ recommendations.
R13 (GPP) Prepare a care plan and forward to the patient’s R24 ("") Offer an intramuscular depot or a short course of
general practitioner within 2 weeks of their clinic appoint­ low-dose oral corticosteroids as a second-line option to treat
ment, noting any specialist advice required (e.g. for changes arthritis/arthralgia in adults with Behçets without any serious
in medication). organ involvement when there is inadequate response
to colchicine.
Mucocutaneous R25 (GPP) Consider nonsteroidal anti-inflammatory drugs
R14 ("") Offer� potent or superpotent topical corticosteroids (NSAIDs) as an alternative to oral corticosteroids when treat­
to treat oral and genital ulcers in people with Behçets if the ing arthritis/arthralgia in people with Behçets without any se­
symptoms are mild, or as adjunctive therapy with systemic rious organ involvement if there is no contraindication.
immunosuppression for more severe disease. Consider the ap­ R26 (GPP) Offer intra-articular corticosteroid injection as
propriate formulation of the topical corticosteroids for oral an option to treat monoarticular or oligoarticular synovitis in
and genital use depending on patient preference and age, as people with Behçets.
well as ulcer location. R27 ("") Offer azathioprine or anti-tumour necrosis factor
R15 (GPP) Consider the triple mouthwash§ for oral ulcera­ therapy as options to treat persistent and refractory arthritis/
tion in people with Behçets. arthralgia in people with Behçets.
§
The triple mouthwash: betamethasone 500 micrograms R28 (") Consider apremilast as an option to treat arthritis/
soluble tablets þ doxycycline 100 mg þ 1 mL nystatin arthralgia in adults with Behçets.
oral suspension. R29 (") Consider methotrexate, mycophenolate mofetil or
R16 (GPP) Consider potent and superpotent corticoste­ azathioprine as options to treat arthritis/arthralgia in people
roids, as a single preparation or in combination with nystatin with Behçets. Caution should be exercised in those with ex­
and neomycin, as treatment for anogenital ulceration in peo­ tensive mouth ulceration due to its potential to worsen with
ple with Behçets above 12 years of age. methotrexate therapy.
R17 ("") Offer� colchicine as a second-line option to treat R30 (") Consider secukinumab as an option to treat arthri­
mucocutaneous lesions in people with Behçets, where topical tis/arthralgia in adults and children aged ≥ 6 years
corticosteroid therapy alone provides inadequate disease con­ with Behçets.
trol. Titrate colchicine dosing gradually to minimize any gas­ R31 (GPP) Consider referral to physiotherapy, occupa­
trointestinal side-effects. tional therapy and/or podiatry, if symptoms require.
R18 ("") Offer� azathioprine or mycophenolate mofetil as
a third-line monotherapy option or as adjunctive therapy for
mucocutaneous lesions in people with Behçets who have Gastrointestinal
poorly controlled symptoms. R32 ("") Offer� oral/intravenous corticosteroids as a first-
R19 ("") Offer anti-tumour necrosis factor therapy as a line option to treat acute flares in people with gastrointesti­
third- line option to treat mucocutaneous lesions in people nal Behçets.
with Behçets who have poorly controlled symptoms and/or R33 ("") Taper� systemic corticosteroids on commencing
with other organ involvement refractory to conventional sys­ 5-aminosalicylic acid, azathioprine or 6-mercaptopurine in
temic therapies. people with gastrointestinal Behçets.
BAD and BSR living guideline for Behçets 2024 79

R34 ("") Offer� 5-aminosalicylic acid as a first-line option R45 ("") Offer anti-tumour necrosis factor therapy as a
to treat flares of mild-to-moderate clinical activity in people second-line option to treat sight-threatening eye disease in
with gastrointestinal Behçets. people with ocular Behçets.
R35 ("") Offer� azathioprine or 6-mercaptopurine as a R46 ("") Offer interferon-α-2a (if available) to treat sight-
first- or second-line option to people with gastrointestinal threatening eye disease in people with ocular Behçets.
Behçets who have moderate-to-severe clinical activity and R47 ("") Offer tocilizumab to people with ocular Behçets
those with large or deep ulcers, to prevent complications (e.g. who have not responded to anti-tumour necrosis factor or in­
perforation, bleeding or obstruction). terferon-α-2a therapies.
R36 (GPP) Consider anti-tumour necrosis factor therapy R48 (") Only consider chlorambucil and cyclophospha­
early in the management approach, as a first-line option for mide as options to treat sight-threatening eye disease in peo­
both induction and maintenance, in people with severe gas­ ple with ocular Behçets when biologic therapy has failed.
trointestinal Behçets or in those with large/deep ulcers (to R49 (GPP) Manage non-sight-threatening eye disease in
prevent complications such as perforation, bleeding or people with ocular Behçets depending on the frequency and
severity of the episodes.

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obstruction).
R37 (") Consider azathioprine or 6-mercaptopurine as a
first-line option to prevent postresection clinical/endoscopic Θ There is insufficient evidence to recommend colchicine
relapses, or perforation/bleeding in people with gastrointesti­ monotherapy in people with ocular Behçets.
nal Behçets.
R38 ("") Offer� anti-tumour necrosis factor dose escala­ Neurological
tion and/or dose-interval reduction in resistant cases, to The following neuro-Behçets recommendations produced via
achieve clinical and endoscopic remission in people with gas­ a prior international neuro-Behçets consensus project10 have
trointestinal Behçets. Concomitant use of immunomodula­ been reviewed and adopted by the GDG.
tors (e.g. azathioprine or 6-mercaptopurine) may achieve
General management of neuro-Behçets
early and sustained clinical and endoscopic response.
R39 ("") Offer� immediate surgery as a life-saving ap­ R50 (GPP) Consider a neuro-Behçets diagnosis in people
proach to people with gastrointestinal Behçets with uncon­ with neurological presentations in the context of other
trolled bleeding, perforation or obstruction. Behçets-defining features (recurrent oral or genital ulcera­
R40 (") Consider systemic corticosteroids and anti-tumour tions, uveitis etc) or after the exclusion of other neurological
necrosis factor agents as a first-line option in people with gas­ conditions and disease mimics. Consider the international
trointestinal Behçets to avoid postresection clinical/endo­ consensus recommendation (ICR) diagnostic criteria for
scopic relapse. neuro-Behçets in adults.10 There are no corresponding crite­
R41 (GPP) Consider any other therapeutic option available ria at present for children and young people.
in inflammatory bowel disease treatment protocols (e.g. uste­ R51 (GPP) When considering a diagnosis of neuro-Behçets
kinumab or vedolizumab), in people refractory to all thera­ take into account:
peutics available for gastrointestinal Behçets.
R42 (") Consider thalidomide as a last resort in people
� the typical parenchymal presentation in people with sus­
with gastrointestinal Behçets refractory to other available pected neuro-Behçets, namely subacute onset of brainstem
treatments. Combined treatment with an anti-tumour necro­ syndrome, cerebral hemispheric syndrome, spinal cord
sis factor therapy may be an option for better outcomes. syndrome or a combination of these, which can manifest
Mandatory monitoring, with neurophysiology and appropri­ through a multitude of signs/symptoms (including oph­
ate contraception and counselling in women and men thalmoplegia, cranial nerve deficit, speech impairment,
patients of childbearing potential, is required. hemiparesis, hemisensory loss, myelopathy, sphincter
symptoms, headaches, meningoencephalitis, encephalopa­
thy, seizures, cognitive impairment, behavioural changes,
etc), as well as its course (i.e. relapsing–remitting pattern
Ocular or a primary or secondary progressive course)
R43 ("") Offer� oral/intravenous corticosteroids as a first- � the nonparenchymal presentation in people with sus­
line option to treat sight-threatening eye disease in people pected neuro-Behçets who present with headaches and vi­
with ocular Behçets. Topical corticosteroids may be copre­ sual impairment secondary to intracranial hypertension,
scribed. Sight-threatening eye disease may be defined as one cerebral thrombophlebitis, cerebral vascular accident, ar­
or more of the following features: terial thrombosis, dissection or aneurysm, usually as a
monophasic illness, although relapses can ensue
� clinically significant vitritis � that neuro-Behçets can present as a combination of paren­
� retinal infiltrate chymal and nonparenchymal forms.
� retinal vascular occlusion
� optic disc swelling
� macular oedema. R52 (GPP) Consider the possibility that headaches in peo­
ple with suspected neuro-Behçets are common and can occur
during flare-ups, in the absence of central nervous system in­
R44 ("") Offer� a steroid-sparing agent (e.g. azathioprine, volvement. Investigate people with Behçets (e.g. brain mag­
methotrexate or a calcineurin inhibitor) along with oral/in­ netic resonance imaging and/or magnetic resonance
travenous corticosteroids for sight-threatening eye disease in venography and lumbar punctures), especially when head­
people with ocular Behçets. aches are severe or incapacitating, progressive, refractory or
80 Ruth Murphy et al.

persistent, or if they are related to visual or neurological relapses or progression) or intolerable side-effects to immu­
symptoms and signs. nosuppressive therapy.
R64 ("") Offer� azathioprine and anti-tumour necrosis fac­
Investigations and assessment tor therapy (infliximab) alongside systemic corticosteroids as
R53 (GPP) Be aware that serological markers for inflamma­ a first-line therapeutic option, to people with neuro-Behçets
tion (i.e. erythrocyte sedimentation rate and C-reactive pro­ who have experienced a major parenchymal episode.
tein) might be normal in people with suspected R65 (") Consider alternative anti-tumour necrosis factor
neuro-Behçets. therapies (e.g. switching from infliximab to adalimumab or
R54 (GPP) Perform magnetic resonance imaging including etanercept) in people with refractory neuro-Behçets.
contrast, and magnetic resonance venography in people with R66 (") Only consider interferon-α (if available) or anti-
suspected neuro-Behçets to investigate parenchymal disease interleukin-6 agents, as alternative therapeutic options in
and cerebral venous thrombosis, respectively, and to help in­ carefully chosen cases, in people with parenchymal neuro-
form the differential diagnosis. Behçets who are refractory to other disease-modifying immu­
R55 (GPP) Offer cerebrospinal fluid (CSF) examination in nosuppressive agents and anti-tumour necrosis factor (TNF)

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people with suspected neuro-Behçets to establish the diagno­ therapy, or if anti-TNF therapy is contraindicated.
sis and exclusion of other pathologies. Note that parenchy­ R67 ("") Offer� a course of high-dose intravenous cortico­
mal neuro-Behçets is usually associated with CSF pleocytosis, steroids to people with nonparenchymal cerebral venous
raised CSF protein and absence of oligoclonal bands; nonpar­ thrombosis neuro-Behçets, followed by a maintenance dose
enchymal neuro-Behçets is associated with elevated CSF pres­ of oral corticosteroids for up to 6 months.
sure. However, a completely normal CSF does not exclude R68 (") Consider azathioprine or anti-tumour necrosis fac­
parenchymal neuro-Behçets. tor therapy, in addition to oral corticosteroids over 6 months
R56 (GPP) Consider monitoring interleukin (IL)-6 cytokine (tapering stage of steroids) to people with active systemic
serum and cerebrospinal fluid (CSF) levels in people with sus­ Behçets, recurrent nonparenchymal neuro-Behçets or a previ­
pected neuro-Behçets. Elevated CSF IL-6 levels are an indica­ ous or concurrent parenchymal neuro-Behçets.
tor of ongoing disease activity. R69 (") Consider anti-tumour necrosis factor therapy to treat
R57 (GPP) Avoid making a diagnosis based exclusively on acute flares in people with nonparenchymal neuro-Behçets (e.g.
asymptomatic neurophysiological findings in people with sus­ cerebral venous thrombosis) in case of recurrence.
pected neuro-Behçets. R70 ("") Avoid� ciclosporin in people with a history of
R58 (GPP) Consider the modified Rankin scale11 to measure neuro-Behçets, due to potential neurotoxicity. If previously
the level of disability for people diagnosed with neuro-Behçets. offered, ciclosporin should be stopped at the first indications
of parenchymal neuro-Behçets involvement.
Treatments
There are no comparative studies on the treatment options Θ There is insufficient evidence of benefit or harm to rec­
for neuro-Behçets. The recommendations below are based on ommend routine use of anticoagulants in people with
limited, lower-certainty evidence and GDG consensus. cerebral venous thrombosis neuro-Behçets. If using
R59 (GPP) Consider induction and maintenance treatments anticoagulants, exclude a systemic aneurysm prior
for people with neuro-Behçets, in line with other neuroin- to initiation.
flammatory conditions. Be aware that patients may already be
on immunosuppressive therapy due to systemic Behçets fea­ Vascular
tures and/or other organ system involvement. Arterial involvement
R60 ("") Offer� a course of high-dose intravenous cortico­ R71 ("") Offer oral corticosteroids and cyclophosphamide
steroids to people in the acute form (first or relapsing attack) pulses or anti-tumour necrosis factor (TNF) as an induction
or those with the subacute form of parenchymal neuro- and maintenance therapy (minimum 2 years), comprising cor­
Behçets, followed by a maintenance dose of oral corticoste­ ticosteroids and azathioprine or continued anti-TNF, to peo­
roids for up to 6 months. In the acute phase, the course of ple with aortic and peripheral arterial involvement associated
high-dose intravenous corticosteroids would enable signifi­ with Behçets.
cant disease suppression or induce remission. R72 ("") Offer� stenting or surgery without delay to symp­
R61 ("") Offer� azathioprine alongside systemic corticoste­ tomatic people with aortic and peripheral arterial involve­
roids to people with neuro-Behçets who have experienced pa­ ment associated with Behçets.
renchymal relapse or have had inadequate response to
maintenance corticosteroids with ongoing systemic Behçets Pulmonary arterial aneurysm
features. Other immunosuppressive alternatives include R73 ("") Offer� oral corticosteroids and cyclophosphamide
mycophenolate mofetil and methotrexate. or anti-tumour necrosis factor as a first-line option to people
R62 ("") Offer� cyclophosphamide or anti-tumour necrosis with pulmonary arterial aneurysm associated with Behçets.
factor therapy combination as a first-line option in addition R74 (") Consider tocilizumab or interferon-α-2a (if avail­
to high-dose intravenous corticosteroids, in the acute or sub­ able) in people with pulmonary arterial aneurysm associated
acute stage, to people with parenchymal neuro-Behçets with with Behçets with inadequate response to oral corticosteroids
severe clinical manifestations or poor prognostic factors (i.e. and cyclophosphamide or anti-tumour necrosis factor agents
at least one of the following: brainstem or spinal cord in­ or if there are contraindications.
volvement and cerebrospinal fluid pleocytosis).
R63 (") Consider anti-tumour necrosis factor therapy early Deep-vein thrombosis
in the management of people with parenchymal neuro- R75 (") Consider oral corticosteroids and/or anti-tumour ne­
Behçets and those with poor disease control (recurrent crosis factor (TNF) as a first-line therapy option in people
BAD and BSR living guideline for Behçets 2024 81

with acute, deep-vein thrombosis or severe/refractory venous around the patient (e.g. carers, family members, employment,
thrombosis associated with Behçets, and maintain on anti- education, social factors or wider healthcare service
TNF or azathioprine therapy for a minimum of 2 years. involvement).
R76 (##) Do not offer� anticoagulants alongside immuno­ R87 (GPP) Offer access to neuropsychological assessment
suppressive therapy in people with deep-vein thrombosis as­ and intervention to people who present with neurological
sociated with Behçets, as the risk of adverse events may symptoms related to Behçets.
exceed the benefits.
R77 (") Consider interferon-α-2a (if available) as a second- Alternative therapies
line option for achieving recanalization and preventing re­ Θ There is insufficient evidence to recommend alterna­
lapse in people with lower-extremity deep-vein thrombosis tive therapies for people with Behçets.
associated with Behçets.
R78 (GPP) Offer a high dose of oral corticosteroids and
azathioprine to people who present with superficial phlebitis Future research recommendations
or deep-vein thrombosis and pyrexia of unknown origin as

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The following list outlines future research recommenda­
soon as possible after other conditions (e.g. infections) have tions (FRRs).
been excluded and a Behçets diagnosis has been made. If the FRR1 A national registry and biobanking to improve phe­
response to corticosteroids is not prompt, add tumour necro­ notyping and treatment outcomes in people with Behçets.
sis factor inhibitors. FRR2 Genotype–phenotype correlation studies to inform a
targeted therapeutic approach to care for people
Conception, pregnancy and breastfeeding with Behçets.
R79 (GPP) Manage pregnancies in women with Behçets in a FRR3 Well-designed studies to support the use of psycho­
multidisciplinary team setting, with both a physician and ob­ logical therapies in a population with Behçets.
stetrician with interests in rheumatology and perina­ FRR4 Well-designed studies to address the needs of chil­
tal medicine. dren and young people with Behçets and their families and to
R80 (GPP) Offer pre-conception counselling to women determine the best approaches to support them from a psy­
with childbearing potential with Behçets to ensure optimiza­ chosocial perspective.
tion of their treatment or medication; in particular, advise FRR5 Clinical trials in children and young people
them about contraception if they are taking thalidomide or with Behçets.
mycophenolate mofetil. FRR6 Establish a minimum dataset for reporting Behçets
R81 (GPP) Provide ultrasound assessment to monitor fe­ in people of all ages, including quality of life and other out­
tal growth. come measures.
R82 (GPP) Suggest that the decision about the mode of de­ FRR7 Whole-exome sequencing to identify genotype–phe­
livery should be made by the patient in consultation with notype correlation in Behçets.
their obstetrician. Caesarean section is not mandated but is FRR8 Well-designed clinical trials to evaluate the efficacy
often advised if there is concern about either genital ulcera­ and safety of neuro-Behçets treatments.
tion or the development of pathergy. FRR9 Establish factors influencing the prognosis of
R83 (GPP) Encourage breastfeeding in all women with neuro-Behçets.
Behçets. If medication has been used during pregnancy, then FRR10 Randomized controlled trials to evaluate the safety
it is almost certainly safe for the mother and baby to take and efficacy of oral Janus kinase inhibitors compared with
while breastfeeding. appropriate interventions commonly used in people
with Behçets.
Psychological
R84 (GPP) Include a clinical psychologist in the multidiscipli­
nary team. People with Behçets should be screened and moni­ 4.0 Algorithm
tored routinely by all relevant healthcare professionals. The recommendations, discussions in the LETR (Appendix
R85 (GPP) Provide general emotional support and consider C), and consensus specialist experience were used to inform
focused interventions, if psychological distress is identified, the algorithm/pathways (Figures 1 and 2).
to support self-management and coping. Consider
‘Motivational Interviewing’ and ‘Solution-Focused Therapy’
approaches to better understand and improve medication ad­ 5.0 Background
herence based on individual presentation and pa­ 5.1 Definition
tient preference. Behçets is named after a Turkish dermatologist, Hulusi
R86 (GPP) Consider psychological formulation-based Behçet, who in 1937 first reported a patient presenting with
approaches via professional psychological practitioners, recurrent mouth and genital ulcers and uveitis.8,12 We now
drawing upon cognitive behavioural therapy (CBT) and know that Behçets occurs worldwide, but is most prevalent in
‘third- wave’ CBT approaches (e.g. Acceptance and Turkey (80–370 cases per 100 000) and Japan (13.5–35 per
Commitment Therapy or Compassion-Focused Therapy), or 100 000), followed by Korea, China, Iran, Iraq and Saudi
a mindfulness-based approach. Other psychological interven­ Arabia.13 It is a rare, multisystem, chronic and recurrent in­
tions (e.g. Eye Movement Desensitization and Reprocessing flammatory condition that can affect blood vessels of any size
Therapy) should be considered for more complex history or and presents as multiple phenotypes.
experiences of Behçets and/or its treatment. Systemic In this guideline we will consider Behçets in all disease types
approaches may also be of benefit, for instance formulations and in people of all ages. Some lesions described in Behçets, such
and/or interventions that incorporate the wider systems as aphthous ulceration, erythema nodosum and pseudoacne,
 82

Figure 1. Management pathway for people with Behçets. For children and young people aged ≤ 16 years this should be within a specialist paediatric or adolescent centre. ASA, aminosalicylic acid; Aza,
azathioprine; CS, corticosteroids; CyP, cyclophosphamide; IFN, interferon; IL, interleukin; MDT, multidisciplinary team; MMF, mycophenolate mofetil; MP, mercaptopurine; MTX, methotrexate; NSAID,
nonsteroidal anti-inflammatory drug; QoL, quality of life; TNF, tumour necrosis factor; TOC, tocilizumab
Ruth Murphy et al.

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BAD and BSR living guideline for Behçets 2024 83

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Figure 2. Stepped-care model for providing psychological care for people living with Behçets. CBT, cognitive behavioural therapy; MDT, multidisciplinary
team; PTSD, post-traumatic stress disorder

may show inflammation without frank vasculitis on biopsy. The can occur, potentially leading to blindness, permanent neuro­
inflammatory skin conditions may be rather nonspecific, but as­ logical injury or major blood vessel involvement.16,17 This
sociated with disease flares and malaise. Childhood onset of drives the need for increased diagnostic awareness in patients
Behçets occurs, but disease prevalence and therapeutic interven­ with a history of recurrent mucosal ulceration, and multidisci­
tions are reported mainly in adult populations.14,15 plinary input to aid prompt diagnosis and effective therapeutic
Presentation is often insidious, often without serological evi­ intervention to prevent organ damage.
dence of inflammation, contributing to both diagnostic chal­
lenge and delay. Typically, it is characterized by recurrent oral 5.2 Epidemiology
and genital ulceration, arthralgia, fatigue and skin symptoms. Due to both the disease rarity and diagnostic difficulty, the
However, more acute presentations of inflammatory eye dis­ true prevalence of Behçets is not known, but it appears to be
ease, and gastrointestinal, neurological and skin involvement highest along the ‘Silk Route’, stretching from the Far East to
84 Ruth Murphy et al.

the Mediterranean. In Western countries, such as the UK and clinical challenge to prompt diagnostic accuracy and effective
USA, Behçets appears to be rarer.15 A meta-analysis of epide­ therapeutic intervention.
miological studies of adults with Behçets estimated a preva­ The most widely cited diagnostic criteria are the ISG crite­
lence of 10.3 per 100 000 (95% CI 6.1–17.7), with higher ria (1990) and the International Criteria for Behçet’s Disease
rates in Turkey (119.8 per 100 000, 95% CI 59.8–239.9) (ICBD; 2006, revised 2013). The ISG suggests that recurrent
than in the Middle East (31.8 per 100 000, 95% CI 12.9– oral ulceration is essential to make a diagnosis of Behçets,
78.4) and Europe (3.3 per 100 000, 95% CI 2.1–5.2).17 along with any two of the remaining four items (genital
A recent, adult study in the Midwest of Ireland estimated ulcers, skin involvement, eye involvement or positive
the point prevalence of Behçets, based on the International pathergy test),22 while the ICBD weighs oral ulceration and
Study Group (ISG) criteria, as 6.2 per 100 000 population.18 genital ulcers more heavily than other items, but does not
A UK study in children aged < 16 years showed a 2-year pe­ make them essential. The ICBD also includes vascular mani­
riod prevalence estimate of 4.2 per million (95% CI 3.2–5.4) festations, which the ISG does not. The ICBD criteria have
and an incidence of 0.96 per million person-years (95% CI proven to be more sensitive, but less specific than the ISG cri­
0.66– 1.41). Male and female individuals are likely to be teria.21 In children, paediatric criteria also exist and ISG and

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equally affected, but Behçets may present with different phe­ ICBD may not perform as well as in adults with Behçets.14,23
notypes in both childhood and adulthood.8 As the diagnosis of Behçets depends on criteria fulfilment,
full diagnosis may not be possible at the initial presentation.
5.3 Aetiology This is more pronounced in the recently designed Korean
The pathology of Behçets remains unclear, but is believed to Study Group’s GIBD diagnostic set.24 Therefore, patients
be an interplay between genetic and environmental factors. with recurrent, mucocutaneous sign(s) and symptoms should
Numerous studies have identified an association with human continue with follow-up to confirm diagnosis and assess dis­
leucocyte antigen (HLA)-B51 in multiple ethnic groups. ease impact and progression.
More recently, an independent association within the major
histocompatibility complex class I region has emerged.17,19 A 5.6 Differential diagnoses
recent publication has suggested that an epigenetic interac­ Behçets presents with many phenotypes, which lends itself to
tion between HLA-B�51 and ERAP1 (endoplasmic reticulum a wide-ranging differential diagnosis (Table 2). The history of
aminopeptidase 1) may increase disease susceptibility.20 recurrent orogenital ulceration is a helpful guide to diagnosis
Common microbes such as herpes simplex virus and cer­ but does not always capture individuals with incomplete dis­
tain streptococcal species have been proposed to activate the ease. Recently described mimics of Behçets include mono­
immune system via heat shock proteins and activation of the genic autoinflammatory diseases such as haploinsufficiency
T helper 17 and interleukin-17 pathways,21 providing tar­ A20.25 In children, the PFAPA syndrome (periodic fever, aph­
geted routes for therapeutic intervention. thous ulceration, pharyngitis, adenitis) is an important differ­
ential, particularly in those with fever.26 As the presence of
5.4 Phenotypic variation aphthous ulcers is a key diagnostic feature in Behçets, condi­
In the UK, the mucocutaneous phenotype, with recurrent oral tions associated with aphthous ulceration are particularly im­
and genital ulceration and variable skin lesions, presents most portant to exclude, such as idiopathic recurrent aphthous and
commonly in people of all age groups including children.8 The genital ulceration, inflammatory bowel disease, coeliac dis­
reported skin lesions are variable and include erythema nodo­ ease, seronegative arthropathies, haematological malignan­
sum, pseudofolliculitis, superficial thrombophlebitis and neu­ cies, Sweet syndrome and systemic lupus erythematosus.27
trophilic dermatoses. Male patients have been reported to
present with papulopustular skin lesions, in contrast to female 5.7 Organ involvement management and
patients, who are more likely to present with erythema nodo­ treatment hierarchy
sum (septal panniculitis)-type skin lesions.16 The GDG set out to provide an up-to-date, holistic and
The QoL of these patients has been significantly reduced, evidence-based approach to optimize the management of peo­
and patients often report fatigue, pain and loss of energy.22 ple with Behçets. By definition, people with Behçets will have
However, there have been no QoL studies in children and more than one organ affected by disease and this can make
young people. Gastrointestinal involvement with ulceration is therapeutic intervention challenging. However, switching off
reported more commonly in patients from Korea and Japan. inflammation in the affected organs is made easier as the se­
Generally, the skin pathergy test is considered to be both sensi­ lected agent is likely to work at multiple sites. Disease may be
tive and specific within Mediterranean and Middle Eastern severe, with organ damage, particularly if there is ocular and/
countries, as well as Japan, but the rate of a positive response or neurological involvement leading to significant morbidity
from the test appears to be declining in some countries.16 This and mortality.
may also reflect a decline in its general clinical application. The degree of disease activity in any organ will direct treat­
ment choice and may be used to characterize the phenotype
5.5 Diagnosis (e.g. neuro-Behçets, mucocutaneous Behçets). While this
Diagnosing Behçets remains a challenge as there are no diag­ guideline covers multiple specialties, the nature of Behçets is
nostic biomarkers or genetic tests. Instead, diagnosis relies on such that multiple sites are often affected in disease flares and
affected individuals meeting prespecified published clinical simultaneously settle during remission. This means that sys­
criteria and the exclusion of disease mimics. Behçets often temic therapies are often indicated and will show efficacy
evolves gradually, meaning that affected individuals may pre­ across several organs as the inflammation settles. In the short
sent with an incomplete phenotype lasting for many years. term, this therapy will often be systemic CS, either intrave­
This natural disease progression challenges the sensitivity and nously or orally. Similarly, for longer-term control, to reduce
specificity of published diagnostic criteria and presents a disease flares, the same steroid-sparing systemic agents will
BAD and BSR living guideline for Behçets 2024 85

Table 2. Main differential diagnoses

Organ/system and specific feature Histology and investigations Differentials

Skin
Erythema nodosum-like lesions More common in female than male patients Other causes of panniculitis
Inflammatory perivascular infiltrate can be seen,
unlike in other types of erythema nodosum
They present as either lobular or mixed sep­
tal and lobular panniculitis
Papulopustular lesions Sterile pustules, pseudofolliculitis, acne- Acne vulgaris
like lesions Folliculitis
Furuncles
Neutrophilic dermatoses Increased neutrophilic infiltrate seen (pyo­ Idiopathic Sweet syndrome and pyoderma
derma gangrenosum is a diagnosis of ex­ gangrenosum
clusion with no specific

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histological features)
Mucosal ulceration
Aphthous oral ulcer (recurrent aph­ Recurrent and painful ulcers affecting the Idiopathic recurrent aphthous ulcers
thous stomatitis) mucosal surface of the lips, soft palate, Aphthous ulcers associated with inflamma­
buccal mucosa and tongue. These may be tory bowel disease
minor or major (heal with scarring)
Aphthous genital ulcer Recurrent and painful ulcers; the labia mi­ Idiopathic recurrent aphthous ulcers
nora and majora are the most commonly Aphthous ulcers associated with inflamma­
affected sites in female patients tory bowel disease
The scrotum and perianal area are the most
commonly affected sites in male patients
Ocular
Anterior uveitis Granulomatous vs. nongranulomatous ker­ Idiopathic uveitis
atic precipitates Chronic anterior uveitis: anterior uveitis is
The bulk of inflammation is seen anterior to not a classic defining ocular finding in
the crystalline lens Behçets, but can be supportive
Intermediate uveitis The bulk of inflammation is seen behind the Intermediate uveitis is not a classic defining
crystalline lens and anterior to the retina ocular finding in Behçets, but can
Significant inflammation can be seen within be supportive
the vitreous in the context of an inflamma­
tory retinal vein occlusion
Posterior uveitis The bulk of inflammation is within the retina Both inflammatory retinal vein occlusions
or choroid and retinal infiltrates are a common ocu­
Inflammatory retinal vein occlusions resem­ lar finding in Behçets
ble a traditional retinal vein occlusion but
can be multifocal and occur in the presence
of intraocular inflammation. While retinal
vein occlusions occur commonly in the gen­
eral population, they are typically a sign of
cardiovascular disease and occur in the
older population
Retinal infiltrates may occur within the inner
retina and cause irreversible retinal de­
struction. Infiltrates may be confused with
an infectious aetiology. Common intraocu­
lar infections should be excluded including
toxoplasmosis, tuberculosis and syphilis
Scleritis and episcleritis Focal or diffuse redness of the sclera or epis­ While scleritis and episcleritis are reported in
clera are usually associated with pain Behçets, they are not commonly thought
or discomfort of as disease-defining events
Other inflammatory causes should be ex­
cluded. Both infections and inflammatory
diseases of collagen can cause scleritis or
episcleritis
Neurological
Brainstem presentation Neuro-Behçets can be differentiated from its Multiple sclerosis, stroke affecting younger
mimics by a combination of characteristic people (< 45 years of age), intracranial
clinical and paraclinical neurological find­ hypertension, meningoencephalitis
ings in addition to the associated sys­ and myelitis
temic features
Myelitis Spinal cord intrinsic signal change Multiple sclerosis
Meningoencephalitis CSF pleocytosis (neutrophils and lympho­ Infectious or other inflammatory causes of
cytes) and raised CSF meningoencephalitis
protein, usually absent oligoclonal bands
(continued)
86 Ruth Murphy et al.

Table 2. (continued)

Organ/system and specific feature Histology and investigations Differentials

Venous sinus thrombosis Venous drainage obstruction on venography Other neuroinflammatory conditions,
antiphospholipid syndrome
IIH (secondary IIH) Raised CSF pressure Idiopathic or primary IIH
Vascular
Arterial aneurysm Abnormal imaging: computed tomography Takayasu arteritis
angiography, MRI angiography, conven­ Atherosclerosis
tional angiography or ultrasound, show­ Treponemal infection
ing aneurysms Ehlers–Danlos syndrome
Echocardiography Marfan syndrome
Turner syndrome
Familial thoracic aortic aneurysms
Deep-vein thrombosis Abnormal duplex venous ultrasonography Prothrombotic clotting disorder Prolonged

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with obstruction Venous drainage obstruc­ inactivity Chemotherapy
tion on venography Pregnancy Obesity
Elevated D-dimer
Factor V Leiden
Gastrointestinal
Typically local, solid, single or a few ileoce­ Mostly ileocecal, isolated, solid (≥ 1 cm) sin­ Crohn disease
cal ulcers on endoscopy. gle or a few (2–5) segmental ulcers. To a GI tuberculosis
Right-lower-quadrant pain is more frequent lesser extent, small aphthous ileocecal or Monogenetic IBDs: e.g. interleukin-10 defi­
and/or prominent than diarrhoea colonic rather segmental ulcers ciency, XIAP deficiency, chronic granulo­
High complication potential (perforation, matous disease (only 10% after the age of
bleeding), up to 30% or more, based on ul­ 18 years)
cer morphology (nonaphthous, large, vol­ Myelodysplastic syndromes (trisomy 8 þ)
cano-type deep ulcers are accepted as NSAID-related aphthous GI lesions
prone to complication) Granuloma formation found during histo­
Involvement of upper parts of GI tube (i.e. pathological examination may be an indi­
oesophageal and gastric) is very rare and cator of either coeliac disease or GI
could not be accepted as GI Behçets, unless tuberculosis
it could not prove as viral (cytomegalovi­ After resection, very early aggressive endo­
rus, herpes simplex virus), acid-related pep­ scopic recurrence at anastomosis may be a
tic ulcer or GERD related consequence of an ongoing inflammation
Diagnosis of GI ulcer (typical or atypical) at the time of the surgery and is commonly
may be time dependent and considered as seen in GI Behçets. In treatment-resistant
definitive, suspected and probable accord­ cases this condition may end with manda­
ing to the Behçets diagnostic criteria tory stoma
Histopathology rarely reveals vasculitis in Perianal fistula is a common indicator for
standard mucosal punch biopsies (frequent coeliac disease. It is either very rare or coin­
sampling inadequacy, tissue insufficiency cidental in GI Behçets and GI tuberculosis
and rapidly smouldering tendency of typi­ Development of enteroabdominal fistula
cal early-stage signs of vasculitis) may arise from either ongoing inflamma­
tion or pre- or postsurgical care following
bowel resection in both GI Behçets and
coeliac disease

CSF, cerebrospinal fluid; GERD, gastroesophageal reflux disease; GI, gastrointestinal; IBD, inflammatory bowel disease; IIH, increased intracranial
hypertension; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; XIAP, X-linked inhibitor of apoptosis protein.

often be used for different body sites. Treatment aims to im­ The performance of classification and diagnostic criteria for
prove the QoL and prevent end-organ damage, such as blind­ Behçets may not be as good in children, and further classifica­
ness, cerebrovascular damage and organ perforation. tion criteria for paediatric disease have been developed,
Systemic CS, intravenous or oral, are often a first-line known as PEDBD.23 Features such as musculo-skeletal and
choice to induce remission for severe disease flares. To main­ GI involvement appear more frequently in children than in
tain remission and spare CS, other systemic agents are then adults, and are not included in the commonly used criteria
used. The drug selection is directed by therapeutic efficacy for Behçets including ISG, ICBD or PEDBD.28 However, a
according to the most vulnerable organ, with primacy given preliminary study has observed a slightly more favourable ac­
to ocular, neurological or visceral involvement. For mucocu­ curacy of ICBD over PEDBD.29
taneous disease, which is the commonest type presenting in The differential diagnoses in paediatric patients are similar
the UK, targeted topical therapies may suffice, but for ongo­ to those in adults, but early age of onset may be indicative of
ing disease impacting QoL, systemic agents may be needed. a monogenetic mimic, or PFAPA.26,28 PFAPA is a noninher­
ited periodic fever syndrome with high fever lasting 3–7 days
5.8 Paediatrics associated with the above symptoms, which reoccurs every
Around 20% of people with Behçets will present in child­ 3–8 weeks. Monogenic autoinflammatory diseases can pre­
hood.28 The mucocutaneous phenotype is the most common, sent as a Behçets phenotype, including haploinsuffi­
whereas vascular and neurological involvement are rare.8 ciency A20.30
BAD and BSR living guideline for Behçets 2024 87

Evidence from clinical trials for treatment of Behçets in Involvement of sexual health clinics can be distressing due to
children and young people is extremely limited, and evidence the misdiagnosis of sexually transmitted infections relating to
is extrapolated from adult trials with adjustments to dosing genital ulceration, along with the disruption this causes
as per trials for other conditions. within relationships.46
Because of the differences in presentation, differential diag­ Cognitive functioning can be impacted, particularly during
nosis and drug dosing, Behçets in children and young people episodes of flare-ups, in both Behçets and neuro-Behçets, typ­
should be managed in a developmentally appropriate service, ically impacting visuospatial function, processing speed,
including access to an MDT with paediatric expertise. This is working memory, encoding and retrieval attention, and exec­
to ensure that health, education, social and psychological utive functioning.47 Disease-related cognitive impairments
needs are addressed to lessen the impact of Behçets in are associated with anxiety and depression.48
this population. Health-related QoL shows significant improvements with
Transition to developmentally appropriate adult services disease treatment.36,39 Overall, a comprehensive understand­
should be well planned and follow National Institute for ing of the psychological and psychosocial challenges faced by
Health and Care Excellence guidance. The NCEPOD

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those with Behçets is essential for providing appropriate sup­
(National Confidential Enquiry into Patient Outcome and port and care.
Death) report31 of transition from child to adult healthcare
services also provides important information and resource.
Tools such as Ready Steady Go32 can facilitate the transition 6.0 Recommended audit points
process. A person-centred approach should be followed, and Current practice now recommends that all patients with
transfer to adult services should be at a time that is right for Behçets are managed in age-appropriate, multidisciplinary
the individual rather than being based on any age threshold. teams at both diagnosis and review. Patients included in this
audit are expected to be drawn consecutively from these clin­
5.9 Genetics ics and, ideally, should be a minimum of 20 or all those
While Behçets is a complex (polygenic) disease (see Section reviewed in the last 12 months.
5.6), monogenetic inborn errors of immunity may present ini­ The audit points are summarized, with an expected
tially with features mimicking Behçets. This is highlighted by, 100% compliance:
but not limited to, haploinsufficiency of A20.30,33 An exten­
sive review identified 12 monogenetic mimics,34 but increas­ 1) All patients are clinically assessed in a multidisciplinary
ingly others are being described, including the recent team appropriate to age and development.
identification of DEX (deficiency of ELF4, X-linked), caused 2) The diagnostic criteria are documented in the notes and
by loss-of-function mutations in ELF4.35 As a result, next- are in line with the 1990 ISG or ICBD diagnos­
generation sequencing (NGS) involving gene panels, whole- tic criteria.
exome sequencing or whole-genome sequencing are used in­ 3) At diagnosis and each follow-up visit, disease extent is
creasingly in the diagnostic investigations for Behçets. One recorded by a systems enquiry leading to site- specific
advantage of this approach is that whole- exome or whole- examination for involvement of the following systems:
genome sequencing can also provide the HLA-B51 status, as � mucocutaneous (oral, genital and skin)
well as excluding a monogenetic Behçets mimic. Early disease � gastrointestinal
onset, positive family history or atypical presentation consti­ � rheumatological
tute ‘red flags’ that should prompt clinicians to consider � ocular
NGS, if available. That said, adult patients may also have � neurological
monogenetic inborn errors of immunity, and thus could also � psychological.
benefit from NGS even with a presentation of Behçets later
in life. 4) An assessment of overall disease activity is made using a
physician’s and patient’s global assessment, or a
5.10 Psychological difficulties in Behçets Behçets-specific disease activity tool.
People with Behçets can experience a range of psychological 5) Evidence that drug therapy is titrated to disease activity
difficulties, with depression and anxiety identified as the and made as a joint decision with the patient.
most prevalent,36 and at higher rates than in the overall pop­ 6) Assessment of disease impact is made using a quality-of-
ulation.37 Psychosocial distress and impact on QoL are asso­ life assessment tool at diagnosis and each follow-
ciated with severity and duration of illness;38,39 however, this up visit.
association remains to be better understood. 7) Patients are provided with a PIL about Behçets
Immune system flaring symptoms can be highly psycholog­ at diagnosis.
ically challenging due to their remitting–relapsing nature.
Persistent fatigue and pain are frequently reported symptoms Appendix N (see Supporting Information) includes the set
that are associated with anxiety, depression and reduced of audit standards, data items and data collection
QoL.36 Therefore, Behçets can impact negatively at personal methodology.
and systemic levels, such as independence,40 social roles,41
ability to eat or maintain pleasure from eating, sexual func­
tioning and body image,42,43 family planning44 and 7.0 External review: stakeholder involvement
employment.45 and peer review
The journey to Behçets diagnosis can also be long, uncer­ The draft manuscript and the Supporting Information were
tain, isolating and stressful, with the potential for experiences made available to the memberships of the BAD and BSR and
of misdiagnosis and extended periods without treatment. to the British Dermatological Nursing Group, Primary Care
88 Ruth Murphy et al.

Dermatology Society, Association of British Neurologists, Appendix D GRADE profiles.

Royal College of Ophthalmologists, British & Irish Society Appendix E Summary of included systematic reviews.
for Oral Medicine, British Society for Sexual Medicine, Royal Appendix F Summary of comparative studies included in
College of Surgeons of England, Vascular Society of Great quantitative and qualitative synthesis.
Britain and Ireland, British Society of Gastroenterology, Appendix G Narrative findings from noncompara­
Association of Clinical Psychologists UK, Royal College of tive studies.
Obstetricians and Gynaecologists, Royal College of Appendix H PRISMA flow diagram.
Paediatrics and Child Health, and Behçet’s UK. Appendix I Critical appraisal of included systematic
All comments were actively considered by the GDG, and reviews—AMSTAR 2.
the guideline was updated, where appropriate. Following fur­ Appendix J Risk-of-bias analysis.
ther revision, the finalized version was signed off by the Appendix K Excluded studies.
BAD’s Therapy & Guidelines Subcommittee and the BSR’s Appendix L Methodology.
Guidelines Steering Group, prior to submission for Appendix M Search strategy.
publication. Appendix N Audit standards, data items and data

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Upon publication in peer-reviewed journals the guideline collection.
will also be freely available to access from the BAD and Appendix O List of clinical trials registered on
BSR websites. [Link].

Data availability
8.0 Limitations of the guideline
The data are available in the Supporting Information.
This document has been prepared on behalf of the BAD and
BSR and is based on the best data available at the time of
writing. It is recognized that under certain conditions it may Funding sources and editorial independence
be necessary to deviate from the guideline and that the results Development of this guideline has been funded independently
of future studies may require some of the recommendations by the British Association of Dermatologists (BAD). No ex­
herein to be changed. Failure to adhere to this guideline ternal factors have detracted from BAD’s organizational and
should not necessarily be considered negligent, nor should editorial independence. The BAD has a strict adherence to its
adherence to these recommendations constitute a defence Sponsorship Policy and Principles.
against a claim of negligence. The systematic review was lim­
ited to publications in English; this was a pragmatic decision, Disclosure statement: The GDG adhered to BAD’s policy for
but the authors recognize this may exclude some important declaration of interests for guideline authors. Further details
information published in other languages. may be requested by contacting guidelines@[Link].
The following interests were declared over the duration of
the guideline development:
9.0 Plans for guideline revision RM is member of an advisory board for Janssen (nonspe­
The proposed literature surveillance will be scheduled at ≤ 6 cific). RJM is (i) a member of advisory boards for AbbVie,
months, with a view to publish (in the absence of a trigger) Chugai, Novartis, Pfizer and Roche (specific); (ii) a speaker
appropriate updates 12 months after publication of the previ­ at international meetings funded by Chugai/Roche, Eli Lilly
ous guideline iteration. and Pfizer (specific); (iii) a director for the National Centre
All recommendations will be treated as living. The litera­ for Behçets Syndrome (specific); (iv) a chief investigator for
ture surveillance may lead to amendments in some recom­ the BioBehçet’s trial (NIHR EME grant) (specific); and (v) a
mendations and/or the addition of new recommendations, grant holder and chief investigator for the phase II trial
requiring issuance of the next iteration of this liv­ ‘Secukinumab in Behçet’s’, with funding provided to
ing guideline. Liverpool University Hospitals NHS Trust (specific). PB (i)
receives consultancy or lecturing fees from Sobi, Novartis
and Roche (nonspecific); (ii) is a local principal investigator
Supporting Information for the EMERALD trial (Sobi) (nonspecific); (iii) is chief in­
Additional Supporting Information may be found in the on­ vestigator of the KDCAAP trial (nonspecific); and (iv) is a
line version of this article at the publisher’s website: trustee of a patient-led charity for Kawasaki disease (nonspe­
Appendix A Living systematic review protocol. cific). AFC¸ (i) participates on advisory boards and talks at
Appendix B Forest plots. meetings for irritable bowel disease funded by AbbVie, MSD,
Appendix C Linking Evidence To the Recommendations UCB Pharma, Takeda, Pfizer, Centurion, Janssen and Mgen
(LETR): (specific); (ii) is head of the Turkish IBD Association, which
receives annual funding from MSD, AbbVie, Takeda, UCB
� Relative values of different outcomes Pharma, Centurion, Mgen, Pfizer and Janssen (specific); and
� Balance between desirable and undesirable effects (iii) receives funding to their clinic from MSD, AbbVie,
� Certainty of evidence Takeda, UCB Pharma, Centurion, Mgen and Janssen, which
� Patient values and preferences provides medical equipment used for Behçets (specific). SSK
� Cost (i) is chairperson for Janssen (nonspecific); (ii) received
� Other considerations speaker fees from LEO Pharma, Janssen and L’Oreal (non­
� List of recommendations. specific); and (iii) has a salary partly funded by a grant
BAD and BSR living guideline for Behçets 2024 89

awarded by the Women’s Dermatology Society and 09. National Institute for Health and Care Excellence. Transition
GLODERM (The International Alliance of Global Health from children’s to adults’ services for young people using health or
Dermatology) (nonspecific). CEP is the UK’s chief investiga­ social care services [NG43]. Available at: [Link]
uk/guidance/ng43 (last accessed 3 July 2024).
tor for the apremilast clinical trial in paediatric Behçets
10. Kalra S, Silman A, Akman-Demir G et al. Diagnosis and manage­
funded by Amgen (specific). JS (i) is a shareholder with ment of neuro-Behçet’s disease: international consensus recom­
Welbeck Health Partners in OneWelbeck Skin and Allergy mendations. J Neurol 2014; 261:1662–76.
Centre (nonspecific) and (ii) is a subinvestigator for a multi­ 11. van Swieten JC, Koudstaal PJ, Visser MC et al. Interobserver
centre open-label phase I study to evaluate the safety, tolera­ agreement for the assessment of handicap in stroke patients.
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in psoriatic arthritis (non- specific); (ii) is a member of an ad­ Opin Rheumatol 2004; 16:38–42.

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visory board for UCB regarding bimekizumab in psoriatic ar­ 14. Kone-Paut I. Behçet’s disease in children, an overview. Pediatr
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This article has been co-published with permission in Rheumatology and British Journal of Dermatology © the British Society for Rheumatology and British
Association of Dermatologists 2024.
All rights reserved. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing
this article.
Rheumatology, 2024, 64, 74–90
[Link]
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