The target population of these recommendations are those patients with severe manifestations that are difficult to treat and that correspond to any of the clinical phenotypes proposed in recent literature. We broadly define difficult-to-treat cases as refractory (from the Latin refractarius: obstinate, pertinacious), i.e., with persistent activity despite conventional treatment. We include within this definition recurrent cases, with recurrent severe manifestations despite conventional treatment. After reviewing the literature, we decided that we should also consider as difficult to treat those patients with particularly severe initial manifestations, in whom the results expected with conventional therapies are unsatisfactory.

To answer the question about enteric BS, neither vedolizumab nor apremilast was included in the medications to be reviewed. However, the search identified 2 references of interest.

Arbrile et al.15 15 published the case of a 49-year-old patient with erythema nodosum, orogenital thrush, and active intestinal involvement despite previous treatment with azathioprine and several biologics (adalimumab, infliximab, golimumab, and certolizumab), which responded to vedolizumab.15 This was administered intravenously at a dose of 300 mg at 0, 2 and 6 weeks, and every 4 weeks thereafter. After the second dose, the patient presented a marked improvement in intestinal, skin and joint symptoms, achieving clinical remission after 6 months of treatment.

In a multicenter series of 51 cases of BS treated with apremilast in Spain,16 a favourable clinical response was described in 2 patients with ileitis.

In the literature review of the question of patients with GI BS, we found a series of isolated case studies in patients who initially suffered from trisomy 8-associated myelodysplastic syndrome and who also had manifestations of GI BS. We asked ourselves if this group of patients would be among the patients for whom we wanted to make the recommendation. When reviewing the articles we found that patients behaved very differently from GI BS, since they did not improve with monoclonal antibodies inhibitors of tumour necrosis factor alpha (TNF-α) and only improved when treating the myelodysplastic syndrome (with bone marrow transplant in many cases), so we considered these cases outside the scope of this recommendations document.17

There are data in the literature of refractory BS successfully treated with alemtuzumab (anti-CD52). One study included 32 patients who achieved partial or complete remission in 84% of cases, with non-negligible AEs (27% infusion reactions and 25% development of symptomatic thyroid disease).18 This drug was not taken into account when developing the recommendations, since the publication did not differentiate patients based on their clinical manifestations, and we therefore cannot assess the response in the different phenotypes of BS.

In the initial approach to these recommendations, we decided to exclude the population of children and adolescents under 18 years of age due to the absence of relevant studies for their general management, and specifically for difficult refractory or severely relapsing cases.19

There are small but relevant differences between young people and adults. In general, paediatric patients take longer to develop the full disease phenotype. GI tract involvement, neurological findings, arthralgias, and a positive family history are more common in children, while genital and vascular lesions are more common in adult patients. Therapeutic recommendations are, so far, similar to those for adults. Although there is considered to be a better prognosis, with a lower severity score and activity index in children, there may be severe cases that may benefit from the recommendations for adults in this document.

Until now, the only set of criteria recommended for paediatric BS is that of the Paediatric Behçet's Disease (PEDBD) study group.20

The pathergy test is not included and oral aphthosis is not considered a mandatory criterion. All symptom categories carry the same weight, due to the lack of knowledge of their respective frequencies in the general paediatric population.

Although the criteria applied in adults, both those of the ISG21 and those of the ICBD,22 can also be used, Batu et al. reported a sensitivity and specificity of 52.9 and 100% for the ISG criteria, and 73.5% and 97.7% for the PEDBD criteria, respectively.23 On the other hand, Ekinci et al. found a sensitivity and specificity of 87.5% and 100% for the ISG criteria, 93.7% and 98.1% for the ICBD criteria, and 93.7% and 96.2% for the PEDBD criteria, respectively.24 Finally, in a patient with atypical PFAPA traits, we must take into account both BS and, in patients with BS traits in early childhood, consider A2025 haploinsufficiency syndrome.

In BS, skin involvement (folliculitis, pseudoerythema nodosum, pyoderma gangrenosum, erythema multiforme or palpable purpura) can be observed in up to 3 out of 4 patients. Although less frequent (30%–50%), there may be joint involvement in the form of inflammatory arthralgias or asymmetric and non-erosive mono/oligoarthritis of large joints, with a predominance in the lower limbs. Treatment must be individualised based on the predominant clinical manifestations, their severity and the preferences of each patient, with the aim of avoiding permanent organic damage. Mucocutaneous and articular manifestations do not confer an increase in mortality from BS, but they do confer great morbidity. In 2008, the EULAR developed the first recommendations for the therapeutic management of patients with BS, subsequently updated in 2018.6,7

Recommendation 1: In patients with BS with refractory or recurrent mucocutaneous phenotype after conventional treatment, the use of apremilast is recommended (Strong recommendation in favour).

Recommendation 1.1: As an alternative, especially in patients with concomitant joint involvement, it is recommended to use TNF-α inhibitory monoclonal antibodies, preferably adalimumab or infliximab (Weak recommendation in favour).

Recommendation 2: In patients with a mucocutaneous and/or joint phenotype BS in whom there is an insufficient response to apremilast and/or to TNF-α inhibitory monoclonal antibodies (adalimumab and infliximab), the use of monoclonal antibodies directed at the interleukin (IL) 12/23 (ustekinumab) or IL-17 (secukinumab) is considered (GCP recommendation).

Recommendation 2.1: Drugs directed against IL-1 (anakinra and canakinumab) are recommended as an alternative in cases resistant to the aforementioned therapies (GCP Recommendation).

Recommendation 3: In patients with BS with predominantly refractory mucocutaneous involvement, the use of tocilizumab is not recommended based on cases in which its use worsened this manifestation (GCP Recommendation).

Relevant clinical considerations:

• •

  Implementation considerations

  • -

    Apremilast, despite being the drug with the best evidence for this manifestation and including an indication for oral ulcers of BS in the technical specifications, does not currently have a reimbursement price in Spain.

  • -

    In the case of TNF-α inhibitor treatments, the DG considers that AEs are not so frequent, but they can be serious. However, they can be minimised with screening protocols for chronic infections and a vaccination programme for immunosuppressed patients:

    • o

      Prior to starting TNF-α inhibitor drugs, and by extension the rest of the biologics, it is very important to screen for tuberculosis with chest x-ray, tuberculin test and/or IGRA as appropriate, as well as lues serologies and hepatitis B and C viruses, and HIV.

    • o

      Previous vaccination for pneumococcus, hepatitis B, seasonal influenza and herpes zoster should be considered before starting treatment, without delaying its administration in severe cases.

• •

  Monitoring and assessment

  • -

    Periodic analyses should be performed and the possibility of optimising treatment should subsequently be assessed in the event of improvement or remission, as well as close monitoring of potential AEs, mainly infections.

The positive results in the RELIEF RCT,26 supported by observational studies (OS) with balance of the results also in favour of its use16,27–29 and the fact that it is the only drug approved with an indication in the technical specifications sheet since 2019 for treatment of oral ulcers in BS, have led the DG to issue a strong recommendation in favour of apremilast as the first line of treatment for refractory mucocutaneous symptoms. Furthermore, TNF-α inhibitors are positioned as an alternative, preferably adalimumab30–33 or o infliximab,32,34–36 especially in patients with concomitant joint involvement. We should highlight the difficulty of implementing apremilast in our setting, since currently, despite having an indication for a specific domain of BS, it does not have a reimbursement price in Spain. Likewise, based on the evidence identified in the SR, which is determined to have low certainty, and the criteria of the DG, other biologics such as ustekinumab37,38 secukinumab,39,40 and lastly anakinra41–44 and canakinumab45 are considered as a therapeutic alternative for the mucocutaneous-articular phenotype. The EULAR 2018 recommendations state that IL-17 inhibition is not effective in the mucocutaneous domain,7 based on a clinical trial in uveitis that ended early due to failure to achieve the primary objective. However, the SR of the literature on which these recommendations are based identified 2 OSs subsequent to the EULAR recommendations that, despite their low quality, led the DG to conclude that secukinumab could be an effective alternative in the mucocutaneous and articular domain without ocular involvement.39,40

The EULAR 2018 recommendations state that IL-6 inhibition (tocilizumab) is not effective in the mucocutaneous domain, and may even worsen lesions, especially oral and genital ulcers.7 Likewise, the EG recommends not using tocilizumab in refractory mucocutaneous involvement based on the few published cases.46–48

EULAR recommends the use of interferon alfa in selected cases of mucocutaneous involvement and recurrent arthritis, but due to the age and low quality of the studies, the high percentage of AEs and the great variability in dosage and doses used,49–53 together with the limited experience in the use of this drug in our area, the DG does not establish any recommendation in this regard, since other safer and more effective therapeutic alternatives exist. Likewise, the absence of evidence on rituximab, limited to a single identified case,54 and limited clinical experience, do not allow us to establish a recommendation on its use in patients with mucocutaneous and articular phenotype of refractory BS.

The prevalence of vascular involvement in people with BS ranges between 8% (Japan) and 62.3% (Morocco). Vascular manifestations can be a serious complication of BS, with considerable morbidity and mortality, especially in young men. It is estimated that between 18% and 29% of patients with BS present this type of manifestations,55 while other estimates speak of 15%–50%.56 BS can affect the entire vascular tree, veins and arteries of all sizes, causing recurrent vascular events, mainly superficial venous thrombosis and deep vein thrombosis of the lower limbs (DVT). It can also cause thrombosis in atypical locations, such as the cerebral venous sinus, suprahepatic veins (Budd-Chiari), intracardiac thrombi and arterial thromboses.

In this context, a deeper understanding of the risks derived from cardiovascular and thromboembolic complications will allow better long-term management of patients with BS. One of the main difficulties in assessing the evidence is the absence of clinical trials and studies that compare different drugs. Although several SRs have been carried out, there are no guidelines or recommendations in this regard.

Recommendation 4: In patients with BS with refractory or recurrent vascular phenotype after conventional treatment, the use of TNF-α, inhibitory monoclonal antibodies, preferably infliximab, is recommended. Another option could be adalimumab (Strong recommendation in favour).

Recommendation 4.1: Its use will also be evaluated in patients with severe vascular involvement at the beginning who require rapid control of inflammation (GCP Recommendation).

Recommendation 4.2: In case of ineffectiveness of TNF-α inhibitors, tocilizumab is recommended as an alternative (GCP Recommendation).

Recommendation 5: In patients with BS with vascular phenotype, with thrombotic manifestations, in addition to immunosuppressive treatment, the following is recommended:

• •

  In cases of venous thrombotic disease, anticoagulation according to the general clinical practice guidelines for the treatment of venous thromboembolism (GCP Recommendation).

• •

  In cases of thrombosis in arterial territories, antiaggregation according to clinical practice guidelines and consensus on the diagnosis and treatment of acute ischemic events (GCP Recommendation).

Relevant clinical considerations

• •

  Implementation considerations

  • -

    In the case of TNF-α inhibitor treatments, the DG considers that AEs are not very frequent, but they can be serious. However, they can be minimised with screening protocols for chronic infections and a vaccination programme for immunosuppressed patients:

    • o

      Prior to starting TNF-α inhibitor drugs, and by extension to the rest of the biologics, it is very important to screen for tuberculosis with chest x-ray, tuberculin test and/or IGRA as appropriate, as well as lues and lues serologies, hepatitis B and C viruses, and HIV.

    • o

      Previous vaccination for pneumococcus, hepatitis B, seasonal influenza and herpes zoster should be considered before starting treatment, without delaying its administration in severe cases.

• •

  Monitoring and assessment

  • -

    Periodic analyses should be performed and the possibility of optimising treatment should be subsequently assessed in the event of achieving improvement or remission, as well as close monitoring of potential AEs, mainly infections in biological therapy and hemorrhagic events in anticoagulant treatment.

  • -

    In the case of vitamin K antagonists, periodic monitoring of the INR should be carried out to adjust the dose of anticoagulant necessary to maintain the INR between 2 and 3.

Systematic search of the literature did not identify any RCTs. Management of the vascular manifestations of BS varies depending on the affected area, and the evidence for therapies is based on OS. Furthermore, there is no clear definition of refractoriness in vascular BS. In recurrent or refractory thrombosis, the DG has issued a strong recommendation in favour of using TNF-α inhibitors, preferably infliximab,32,34,57–74 although adalimumab can also be used,32,66,67,75,76 despite the low quality of the evidence identified. The clinical experience of favourable use and the seriousness of these patients, in many cases doomed to a potentially fatal outcome, led the DG to reach this agreement. If the TNF-α inhibitors fail, some case series seem to indicate that tocilizumab may be an alternative.77,78 In repeated DVT, immunosuppressive therapy is crucial to prevent relapses and reduce the risk of complications with post-thrombotic syndrome (symptoms and signs of chronic and disabling venous insufficiency).79 There is no consensus on the duration of TNF-α inhibitor treatment after achieving clinical remission in BS and relapses can occur at any time, which justifies close follow-up. It also seems prudent to prolong TNF-α inhibitor treatment, especially in patients with vascular and neurological manifestations.76 The DG, based on its clinical experience and low-quality studies has considered issuing a GCP recommendation in favour of the use of TNF-α inhibitors in cases with severe vascular involvement at the beginning, and another in favour of the use of tocilizumab as an alternative treatment when these are ineffective.

Anticoagulant treatment of thrombotic manifestations of BS remains controversial. The 2018 EULAR recommendations do not recommend anticoagulants to prevent DVT relapses, only in refractory cases and cerebral sinus thrombosis. After carrying out a SR in this regard and taking into account the opinion of a haematologist expert in coagulation, the DG agreed on long-term anticoagulation for patients with BS and recurrent venous thrombosis,80 while opting for antiaggregation for patients with thrombosis in arterial territories.81,82 Situations where we must add anticoagulant therapy to immunosuppressive treatment are DVT, Budd-Chiari, cerebral venous sinus thrombosis and intracardiac thrombosis, always after screening for the risk of bleeding (rule out associated pulmonary aneurysms). The duration of anticoagulation is unclear; After an initial period of 3–6 months, the thrombotic and/or hemorrhagic risk must be weighed on an individual basis and take into account that BS can be considered a risk factor to prolong therapy indefinitely, at least while the disease is active. Reperfusion therapies (mechanical or pharmacological thrombolysis) in severe cases of thrombosis and reconstructive surgery or embolisation in arterial aneurysms may be necessary and should be performed, whenever possible, after the inflammation is controlled with immunosuppressants to reduce postoperative complications.83

Nervous system involvement in Behçet's disease ranges between 5.3% and 10% of patients depending on the series,84 and is usually preceded by other forms of the disease. The central nervous system is the most frequent site of neurological involvement. The peripheral nervous system can also be affected, usually subclinically.85

Depending on the main location of the lesions in the central nervous system, 2 main patterns are distinguished: the parenchymal pattern and the vascular (non-parenchymal) pattern. The parenchymal type is more prevalent, appearing in 20%–60% of cases. It is characterised by small inflammatory lesions in the brain stem, hemispheres, basal ganglia, spinal cord, and meninges. These lesions can cause symptoms due to cortical involvement, pyramidalism or behavioural disorders.86 Sensitive symptoms, movement disorders and epilepsy have been described.87,88 Its acute onset is associated with a good response to treatment, but its chronicity can cause brain atrophy and predicts a more aggressive evolution.89 The spinal cord may also be affected, either due to contiguity of the lesions or in isolation, which constitutes a poor prognostic factor and the most common form of which is multifocal transverse mielitis.90 Treatment of neurological-parenchymal involvement in BS is a priority to avoid neurological and cognitive sequelae.

Recommendation 6: In patients with BS with refractory or recurrent neurological-parenchymal phenotype after conventional treatment, the use of TNF-α inhibitors is recommended, preferably adalimumab or infliximab (Strong recommendation in favour).

Recommendation 6.1: When TNF-α inhibitors are ineffective, the DG recommends the use of tocilizumab, despite the limited evidence available. Another possible therapeutic option is rituximab (GCP Recommendation).

Relevant clinical considerations:

• •

  Implementation considerations

  • -

    In TNF-α inhibitor treatments, the DG considers that AEs are not very frequent, but they can be serious. However, they can be minimised with screening protocols for chronic infections and a vaccination programme for immunosuppressed patients:

    • o

      Prior to starting TNF-α inhibitor drugs, and by extension the rest of the biologics, it is very important to screen for tuberculosis with chest x-ray, tuberculin test and/or IGRA as appropriate, as well as lues serology, hepatitis B and C viruses, and HIV.

    • o

      Previous vaccination for pneumococcus, hepatitis B, seasonal influenza and herpes zoster should be considered before starting treatment, without delaying its administration in severe cases.

    • o

      Before starting rituximab and during follow-up, immunoglobulin levels should be determined.

• •

  Monitoring and assessment

  • -

    Periodic analyses must be performed and the possibility of optimising treatment should be subsequently assessed in case of achieving improvement or remission, as well as close monitoring of potential AEs, mainly infections.

EULAR 2018 recommends TNF-α inhibitor drugs as the first line in severe disease or in refractory patients, without offering therapeutic alternatives. For our part, based on the limited evidence identified68,91–95 and on the clinical experience of the DG, TNF-α inhibitors are recommended in BS with refractory neurological-parenchymal phenotype, without being able to establish priority when choosing between them, since no studies have been identified that compare the use of different TNF-α inhibitors in the study population, although there are more data with adalimumab or infliximab. Differentially and after reviewing the existing literature, the use of tocilizumab as a second line is recommended.96–99 Rituximab is considered as the last therapeutic option, despite the few patients described in the literature and the various drug administration guidelines,100–103 which are not equivalent to those used in our healthcare context. Finally, the DG considers that the limited evidence available95 and the little experience in this group of patients with etanercept do not allow making a recommendation on its use.

The DG considers that since all the biological drugs described are not approved in the technical specifications for the health condition analysed and authorisation from the hospital management is necessary for their use, complications may arise at the time of their implementation, which may vary in each centre.

The prevalence of GI manifestations in BS varies widely according to geographical distribution, ranging between 3% (Turkey, India) and 35%–50% (United Kingdom and Japan). From a pathogenic point of view, 2 types of involvement have been described: a vasculitis mainly of capillaries and venules that leads to the formation of ulcers due to inflammation of the digestive mucosa, and vasculitic involvement of the mesenteric arteries that causes intestinal ischaemia (intestinal angina or intestinal infarction).104 The most common complication is the appearance of single or multiple ulcers, typically volcano-shaped, which are usually located in the ileal or ileocecal region (although they have also been described in the oesophagus and colon). The patients present with abdominal pain and episodes of sometimes bloody diarrhoea, which can lead to acute or chronic complications (perforation, massive haemorrhage, obstruction and development of fistulas). They generally occur between 4.5 and 6 years after the appearance of oral ulcers.

The appearance of GI manifestations in BS is associated with a poorer prognosis, with a significant increase in morbidity and mortality. Between 33% and 62% of patients do not respond adequately to conventional treatment with systemic glucocorticoids, mesalazine and azathioprine (there is also limited experience with calcineurin inhibitors).105–107 Furthermore, among patients who respond to this first line of treatment, 25% relapse after 2 years, a percentage that increases to 43%–49% at 5 years.105–107

With conventional treatment, it is estimated that around one third of patients with GI involvement end up requiring surgery due to perforation, massive haemorrhage, obstruction, or development of fistulas.108–110 Hence the need to identify alternative treatments that are effective in refractory or recurrent cases.

Recommendation 7: In patients with BS with refractory or recurrent GI involvement after conventional treatment, the use of TNF-α inhibitory monoclonal antibodies is recommended, preferably adalimumab or infliximab (Strong recommendation in favour)

Recommendation 7.1: Its use will also be evaluated in patients with severe initial GI involvement who require rapid control of inflammation (GCP Recommendation).

Recommendation 7.2: In cases refractory to TNF-α inhibitors, evaluation of the use of tofacitinib is recommended, individualising the decision (GPC Recommendation).

Relevant clinical considerations

• •

  In TNF-α inhibitor treatments, the DG considers that AEs are not very frequent, but they can be serious. However, they can be minimised with screening protocols for chronic infections and a vaccination programme for immunosuppressed patients:

  • o

    Prior to starting TNF-α inhibitor drugs, and by extension the rest of the biologics, it is very important to screen for tuberculosis with chest x-ray, tuberculin test and/or IGRA as appropriate, as well as lues serology and hepatitis B and C viruses, and HIV.

  • o

    Previous vaccination for pneumococcus, hepatitis B, seasonal influenza and herpes zoster should be considered before starting treatment, without delaying its administration in severe cases.

• •

  Monitoring and assessment

  • -

    Periodic analyses should be performed and the possibility of optimising treatment should subsequently be assessed in the event of improvement or remission, as well as close monitoring of potential AEs, mainly infections.

The EULAR 20187 recommendation and the 2020111 Japanese Society of Gastroenterology recommendation is for the use of TNF-α inhibitors in patients with refractory or recurrent GI involvement. The EULAR7 recommendations also contemplate its use as the first therapeutic step in serious initial cases that require rapid control of inflammation, since clinical and endoscopic improvement has been observed in a high percentage of cases. In the same sense, the DG has issued a strong recommendation in favour of its use in these patients, based on the evidence from a meta-analysis112 and several OS,113–115 and on their clinical experience. In those patients with a refractory or recurrent course despite treatment with TNF-α inhibitors (adalimumab or infliximab), the DG recommends the use of tofacitinib, always individualising the decision. Although the evidence is scarce, in the majority of cases with refractory or recurrent intestinal BS published to date, a favourable response is achieved, both clinical and endoscopic.116–118

In the opinion of the DG, it is foreseeable that rescue treatment in refractory cases will lead to substantial savings in resources by achieving better control of the disease activity, avoiding the development of complications and the need for surgery due to perforation, massive haemorrhage, obstruction or fistulas, and hospital admissions. Furthermore, biosimilars of infliximab and adalimumab are currently available at an acceptable economic cost. The DG considers that it is likely that the treatment of GI manifestations with TNF-α inhibitors (adalimumab and infliximab) will be generally accepted by patients and prescribers, since these are drugs with experience in their use in other diseases, with an acceptable safety profile and are generally used in patients with refractory and/or severe involvement who require rapid control of inflammation. In terms of feasibility, the indication for biological drugs (infliximab and adalimumab) and tofacitinib is outside the technical specifications. Since authorisation from the hospital management is necessary for its use, there may be obstacles when implementing these recommendations. The DG considers that the availability of recommendations such as these, endorsed by scientific societies, is an authoritative argument to justify the request.