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Recommendations for the Management of Neuro-Behçet's Disease by the Japanese National Research Committee for Behçet's Disease

Objective Brain parenchymal involvement in Behçet's disease (BD) (neuro-Behçet's disease, NB) can be classified into acute type (ANB) and chronic progressive type (CPNB) based on differences in the clinical course and responses to corticosteroid treatment. The present study developed evidence-based recommendations for the management of NB. Methods The task force of the research subcommittee consisted of seven board-certified rheumatologists (one was also a board-certified neurologist) and three board-certified neurologists. First, several clinical questions (CQs) were established. A systematic literature search was performed by The Japan Medical Library Association in order to develop recommendations. The final recommendations for each CQ developed from three blind Delphi rounds, for which the rate of agreement scores [range 1(strongly disagree)-5(strongly agree)] was determined through voting by the task force. Results A flow chart of the algorithm was established for the management of ANB and CPNB. Thirteen recommendations were developed for NB (general 1, ANB 7, CPNB 5). The strength of each recommendation was established based on the evidence level as well as the rate of agreement. Conclusion The recommendations generated in this study are based on the results of uncontrolled evidence from open trials, retrospective cohort studies and expert opinions, due to the lack of randomized clinical trials. Nevertheless, these recommendations can be used for international studies, although verification by further properly designed controlled clinical trials is required.

Intern Med 59: 2359-2367, 2020 DOI: 10.2169/internalmedicine.4705-20 plications in BD and is called neuro-Behçet's disease (NB) (1,2). There has been accumulating evidence that NB can be classified into acute type (ANB) and chronic progressive type (CPNB) based on differences in the clinical courses as well as in responses to corticosteroid treatment (3,4), as ANB responds well to corticosteroids and usually runs a self-limiting course, while CPNB is characterized by intractable neuro-behavior changes and cerebellar ataxia that progress despite high doses of corticosteroids or immunosuppressive drugs, including azathioprine and cyclophosphamide (5)(6)(7).
Recently, the first systematic review and meta-analysis was performed with 10 studies to discriminate the clinical presentation of ANB and CPNB, including 205 ANB cases and 111 CPNB cases (8). The study revealed that a fever and elevated cerebrospinal fluid (CSF) cell count were characteristic of ANB, whereas CPNB was characterized by sphincter disturbances, ataxia, dementia, confusions, brain stem atrophy and abnormal magnetic resonance imaging (MRI) findings in the cerebellum (8). Thus, the study has confirmed the importance of recognizing ANB and CPNB separately for the appropriate management of NB patients (8).
The diagnostic criteria for ANB and CPNB were generated in 2013 based on the results of a multicenter clinical survey performed by the Behçet's Disease Research Committee of the Ministry of Health, Labor and Welfare of the Japanese Government (Supplementary material) (3). However, in the 2018 update of the EULAR recommendations for the management of Behçet's syndrome (Behçet's disease), recommendation 9 referred to the treatment of acute attacks of parenchymal involvement of CNS, corresponding to ANB (9), with no recommendation for CPNB included (9). Notably, the clinical entity of CPNB has been confirmed by the above-mentioned meta-analysis (8). Furthermore, there have been several related publications with new data on treatment of CPNB (7,(10)(11)(12)(13). It is therefore necessary to update recommendations for NB with addition of CPNB.
The present study developed evidence-based recommendations for the management of NB in light of recent findings from new studies.

Study overview and patient and public involvement.
The operating process for developing recommendations followed the procedure proposed by the Medical Information Network Distribution Service (Minds) (14). Institutional review board approval and patient consent were not required because of the review nature of this study. Thus, patients and the public were not involved in this study. The study was carried out as a part of the development of 2020 Japanese Society for BD (JSBD) Clinical Practice Guidelines for BD.

Organization of a task force
Within the Behçet's Disease Research Committee of the Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare of the Japanese Government, a task force of the research subcommittee for NB was organized. The task force consisted of seven Japanese boardcertified rheumatologists (one was also a Japanese boardcertified neurologist) and three Japanese board-certified neurologists.

Clinical questions (CQs)
The task force set 15 CQs on NB-related clinical issues, including 1 general question on the definition of NB in the Japanese diagnostic criteria and 14 questions on the management of ANB and CPNB, along with the generation of the algorithm for the management of NB. The questions were formulated into Population, Intervention, Comparison and Outcome (PICO) questions for the literature review.

Systematic review
A literature search was performed by The Japan Medical Library Association (JMLA) using the following medical databases; Cochrane Database of Systematic Reviews, Pub-Med/Medline, The Cochrane Library and Igaku Chuo Zasshi (ICHUSHI) of the Japan Medical Abstracts Society (JA-MAS), based on English or Japanese keywords listed from each PICO formatted CQ. Two researchers (SH, HK) screened the articles for possible inclusion independently. The final inclusion was decided after discussion between the two researchers. The strength of body of evidence for each clinical outcome was evaluated according to the methods proposed by Minds (14), such as A (strong), B (moderate), C (weak) and D (very weak).

Generation of recommendations
Draft recommendations for each CQ proposed by the two researchers through their systematic review were presented to the task force members during a half-day consensus development conference. During the conference, these draft recommendations were discussed and modified accordingly. The modified recommendations were then further refined through three blind Delphi rounds. Consensus was obtained explicitly through voting with the level of agreement, such as 1 (strongly disagree), 2 (disagree), 3 (agree with conditions attached), 4 (agree) and 5 (strongly agree) for each recommendation (Table 1). It had been decided in advance that such recommendation that obtained the averaged level of agreement of less than 4.0 was declined. As a result, two CQs were dropped due to poor agreement scores.
For each surviving CQ, recommendations made by the committee were presented, followed by the evidence level, the agreement level of the 10 task force members and the strength of each recommendation according to Minds (Table 1) (14). The strength of each recommendation was established based on the evidence level as well as on the rate of agreement.

The external evaluation and public comments
Public comments on the draft of recommendations were collected from the external evaluation by the Japan College of Rheumatology and JSBD. Revised recommendations were prepared with consideration of the public comments.

Results
In Figure, the flow chart of the algorithm for the clinical practice for ANB and CPNB is presented. In the flow chart, various points of emerging CQs requiring answers are indicated. As summarized in Table 2, 13 CQs related to the diagnosis and management of NB were generated (general 1, ANB 7, CPNB 5).

General aspect
CQ1. What is the definition of "moderate or severe" CNS manifestations described in the Japanese diagnostic criteria for BD?
All cases that meet the diagnostic criteria for ANB or CPNB should be included in the category of "moderate or severe" CNS manifestations.
ANB is characterized by attacks of inflammatory lesions in brain parenchyma and/or meninges, detected as highintensity areas in T2-weighted images or fluid attenuated inversion recovery (FLAIR) images on MRI (3). Approximately 40% of patients with ANB have been shown to re-lapse without adequate treatment (15,16). Furthermore, severe attacks can sometimes result in permanent damage or disability despite extensive treatment (2,4,6). By contrast, CPNB is characterized by slowly progressive dementia and/ or cerebellar ataxia with persistent elevation of CSF interleukin-6 (IL-6), leading to permanent bed-ridden disability or death without appropriate treatment (3,12). While corticosteroids, cyclophosphamide and azathioprine are not effective at all, low-dose methotrexate (MTX) and infliximab have been shown to be effective in preventing the progression of the neuropsychological manifestations (7,(11)(12)(13).
Therefore, those patients who meet the diagnostic criteria for ANB or CPNB (3) should be defined as patients with "moderate or severe" CNS manifestations and should be treated with appropriate immunosuppressive reagents.

CQ2. How should the dose of corticosteroids be determined in acute-phase treatment of ANB?
If administration of prednisolone at a dose ! 20 mg/day (oral or intravenous) has an insufficient effect, high-dose therapy, including steroid pulse therapy, should be considered.
Corticosteroids are the gold standard for treating acutephase attacks, although they do not prevent recurrence of attacks (1,3,15,16). For acute attacks of ANB, prednisolone at a dose ! 20 mg/day should be given first (3,16). Higherdose corticosteroids, including pulse therapy, need to be considered in patients with inadequate responses. However, it should be remembered that higher doses of corticosteroids may increase the frequency of side effects, such as aseptic necrosis of the femoral head. After the attacks subside, the doses of corticosteroids should be decreased gradually over two to three months in order to prevent relapses of ANB as well as ocular attacks (17).
After the acute phase of ANB, while the dose of corticosteroids is decreasing, colchicine should be started, since the efficacy of colchicine in preventing relapses of further attacks of ANB has been noted (15). However, the drug should be given under careful consideration of its risk and benefit for patients.

CQ3. Should infliximab be used in acute-phase treatment of ANB?
If the effects of corticosteroids at a moderate or higher dose are insufficient, concomitant use of infliximab should be considered.
There have been no reports indicating that infliximab is effective in the acute phase of ANB without corticosteroids. Corticosteroid pulse therapy or addition of infliximab should be considered when moderate or higher doses of corticosteroids show inadequate effects. However, it should be noted that no controlled study has assessed the effects of the addi-tion of infliximab to corticosteroids in ANB, although there are some reports of single cases, case series or uncontrolled prospective studies (18)(19)(20)(21). Furthermore, since the safety of infliximab in ANB is not established, the risks and benefits should be carefully evaluated in each patient before introducing infliximab.

CQ4. When and how long should colchicine be used to prevent attack in ANB?
Administration of colchicine (1.0-2.0 mg/day) should start immediately after the first attack and continue for 5 years.
Previous studies have shown that, in patients receiving colchicine, relapse was very rare after 5 years from the initial ANB attack (15). Therefore, it is recommended that colchicine (1.0-2.0 mg/day) be continued for 5 years (15). However, the drug should be given under careful consideration of its risks and benefits for each patient, as mentioned in CQ2.

CQ5. What kind of treatment should be provided to patients with ANB in whom cyclosporine is used?
Cyclosporine should be discontinued. For ocular involvement, the use of infliximab should be considered.
Cyclosporine is effective in preventing uveitis attacks (22). However, cyclosporine is often associated with the development of acute neurological attacks, which should What is the definition of "moderate or severe" CNS manifestations" described in the Japanese diagnostic criteria for BD?
All cases that meet diagnostic criteria* for ANB and CPNB should be included in the category of "moderate or severe" CNS manifestations.
How should the dose of corticosteroids be determined in acute-phase treatment of ANB disease?
If administration of prednisolone at a dose ≥20 mg/day (oral or intravenous) has an insufficient effect, highdose therapy, including steroid pulse therapy, should be considered.   5 What kind of treatment should be provided to patients with ANB in whom cyclosporine is used?
Cyclosporine should be discontinued. For ocular involvement, the use of infliximab should be considered Are MTX, cyclophosphamide, and azathioprine effective for treatment and prevention of attacks in patients with ANB?
Since effects of these drugs for prevention of relapse are thought to be lower than those of colchicine, active use of these drugs is not recommended. When an attack relapses, even after the use of colchicine, treatment with infliximab should be considered.

4.20 C1
8 How is the transition from ANB to CPNB confirmed?
Careful evaluation of neurological findings and brain MRI with CSF IL-6 is required after patients with ANB improve on withdrawal or reduced doses of corticosteroids. Are patients with CPNB always accompanied by precedent ANB?
Symptoms of ANB do not necessarily precede CPNB.   The goals should be the control of CSF IL-6 at a low level, no progression of symptoms, and no progression in atrophy of the brainstem on MRI. How frequently should brain MRI and measurement of CSF IL-6 be performed in treatment of CPNB?
These examinations should be performed as needed until the therapeutic regimen is firmly established. Thereafter, brain MRI should be performed at least once a year, while CSF IL-6 should be examined once a year or more frequently if possible. be regarded as ANB (5,15,23). In fact, there were no significant differences in the demographic features, clinical symptoms, MRI findings, treatment regimens or outcomes between patients with cyclosporine-related ANB and cyclosporine-unrelated ANB (15). It has been recently demonstrated that patients with cyclosporine-related ANB showed almost no relapse by the discontinuation of cyclosporine, whereas approximately 40% of patients with cyclosporine-unrelated ANB experienced recurrent ANB attacks (15). Therefore, the discontinuation of cyclosporine is strongly recommended for patients with cyclosporine-related ANB (9,15). Tacrolimus, another calcineurine inhibitor, might have similar neurotoxic effects (15). Infliximab should be considered for patients who are at risk of recurrence of uveitis attacks after the discontinuation of cyclosporine. However, since the safety of infliximab in ANB has been established, the risks and benefits should be carefully evaluated in each patient before its introduction.

CQ6. Are MTX, cyclophosphamide and azathioprine effective for treating and preventing attacks in patients with ANB?
Since the effects of these drugs for the prevention of relapse are thought to be lower than those of colchicine, the active use of these drugs is not recommended.
There has been no evidence for the efficacy of MTX, cyclophosphamide or azathioprine for preventing ANB attacks. It has been shown that the effects of colchicine in preventing relapses of ANB were significantly better than those of MTX and azathioprine (15). Indeed, colchicine was found to decrease the relapse rates in patients with cyclosporineunrelated ANB [hazard ratio (HR): 0.1672, 95% confidence interval (CI): 0.0089-0.9138], whereas the effects of MTX or azathioprine were not significant (15). In another report, a trend toward a shorter event-free survival was observed in patients treated with intravenous cyclophosphamide compared to those treated with azathioprine (16). However, the event-free survival rate in patients with cyclophosphamide was 56% at 5 years as well as at 10 years (16), whereas that in patients receiving colchicine was 90% at 5 years as well as at 10 years (15). Thus, it appears that cyclophosphamide might not be as effective as colchicine in preventing relapse of ANB, although differences in the background characteristics of the patient population between the two studies might have affected the results (15,16).
However, the prolonged use of cyclophosphamide is now discouraged due to its carcinogenicity (24). Collectively, colchicine is the best choice for preventing relapses in patients with ANB. Of course, colchicine should be given under careful consideration of its risks and benefits for each patient, since the safety of colchicine is not established in ANB.

CQ7. Is infliximab effective for prevention of attacks in patients with ANB?
When an attack relapses, even after the use of colchicine, treatment with infliximab should be considered.
Infliximab has been demonstrated to prevent the development of uveitis attacks in BD by a randomized control trial (RCT) (25). It makes sense to expect infliximab to exert similar effects to prevent ANB attacks. Therefore, infliximab should be considered in patients who have relapses of ANB attacks, even when using colchicine. In fact, a recent prospective study showed the efficacy of infliximab in preventing attacks of ANB (26). However, the effect of infliximab on the prevention of ANB attacks needs to be examined through RCTs in the future.
Again, since the safety of infliximab in ANB is not established, the risks and benefits should be carefully evaluated in each patient with ANB before its introduction.
CQ8. How is the transition from ANB to CPNB confirmed?
The careful evaluation of the neurological and brain MRI findings with the measurement of CSF IL-6 is required after patients with ANB improve and corticosteroids are reduced to <10 mg/day. Following acute attacks of ANB, corticosteroids should be gradually tapered with a careful evaluation of the neurological, brain MRI and CSF findings. In patients with CPNB, high doses of corticosteroids can reduce the levels of CSF IL-6 transiently. Thus, it is possible that prednisolone ! 10 mg/day might result in a false negative for CSF IL-6. Therefore, after patients with ANB improve and corticosteroids are reduced to <10 mg/day, the CSF IL-6 level should be examined. If it exceeds 17 pg/mL at this point, the CSF IL-6 level should be examined again in ! 2 weeks (3,5). If CSF IL-6 still exceeds 17 pg/mL at the second examination, a diagnosis of CPNB should be made (3). If there is apparent brainstem atrophy with CSF IL-6 ! 17 pg/mL at the first examination, a diagnosis of CPNB can be made without waiting for the results of the second CSF evaluation (Figure) (3).

CQ9. Are patients with CPNB always accompanied by precedent ANB?
Symptoms of ANB do not necessarily precede CPNB. Approximately 90% of patients with CPNB had a history of ANB (3,5). Preceding symptoms of ANB might be mild headache alone, although some patients with CPNB show progressive neuropsychiatric manifestations without evident subjective symptoms of ANB (3,4).
Whether or not preceding symptoms are evident, the CSF IL-6 levels in addition to the MRI findings should be examined for patients who present with slowly progressive neuropsychiatric changes, cognitive dysfunction or cerebellar ataxia (3).
For patients with brainstem atrophy on MRI, spinocerebellar degeneration needs to be ruled out. Since this condition does not show persistent elevation of CSF IL-6 levels, the repeated determination of the CSF IL-6 level with a ! 2week interval is helpful for the differential diagnosis of CPNB (3,5).

CQ10. How much should CSF IL-6 be decreased under treatment for CPNB?
CSF IL-6 should be decreased to <17 pg/mL as soon as possible.
On comparing patients with ANB in the convalescent phase to those with CPNB, the CSF IL-6 levels were significantly higher in the CPNB patients. A receiver operating characteristics (ROC) analysis indicated that CSF IL-6 can discriminate the CPNB from ANB in the convalescent phase with a sensitivity of 92.0% and specificity of 94.7% at a cut-off value 17.0 pg/mL (3). Based on this evidence, it is recommended that treatment be performed to reduce the CSF IL-6 level to <17 pg/mL as soon as possible (3). However, even in cases with a CSF IL-6 level ! 17 pg/mL, careful observation without changes in the treatment regimen may be sufficient, provided neurological manifestations and brainstem atrophy on MRI do not progress. In such cases, the CSF IL-6 levels should be examined at least once every six months to one year.

CQ11. When should infliximab be introduced for the treatment of CPNB?
Infliximab should be introduced immediately when there is no improvement in the neurological manifestations and the CSF IL-6 levels has not been decreased to <17 pg/mL with the administration of MTX at the maximum feasible dose.
MTX should be started immediately when the diagnosis of CPNB is made (7,12). The dose of MTX should be increased until therapeutic effects can be confirmed (i.e. until CSF IL-6 is reduced below 17 pg/mL), as is the case with treatment of rheumatoid arthritis.
If there is no improvement in the neurological manifestations with CSF IL-6 levels still exceeding 17 pg/mL after the administration of MTX at 16 mg/week, or if the dose of MTX cannot be increased to the level needed to achieve an adequate response due to side effects, the immediate use of infliximab should be considered (Figure) (11). It should be remembered that CPNB progresses most extensively in an irreversible manner shortly after the onset (27).

CQ12. How should the therapeutic goals be determined for patients with CPNB?
The goals should be no progression of symptoms, control of CSF IL-6 at a low level and no progression of atrophy of the brain stem on brain MRI.
Treatment to target for CPNB should include a lack of progression of neurological manifestations (neuropsychiatric changes, cognitive dysfunction or cerebellar ataxia) as well as a lack of progression of brainstem atrophy on MRI (11,27). A previous report found no progression of brainstem atrophy as long as CSF IL-6 levels were kept low (27). Therefore, CSF IL-6 might be a surrogate marker for 'treat to target'. In patients with advanced CPNB who have severe dysphagia and/or heavy cognitive dysfunction, infectious disease measures are necessary.
CQ13. How frequently should brain MRI and CSF IL-6 measurements be performed for the treatment of CPNB?
These examinations should be performed as needed until the therapeutic regimen is firmly established. Thereafter, brain MRI should be performed at least once a year, while CSF IL-6 should be examined once a year or more frequently if possible.
In order to establish the treatment regimen to achieve the treat to target goal, brain MRI and CSF IL-6 measurements need to be performed as frequently as required (3,11). In rheumatoid arthritis, effect attenuation and second failure of MTX and infliximab have been noted. Therefore, in CPNB, the lack of progression of neurological manifestations (neuropsychiatric changes, cognitive dysfunction or cerebellar ataxia) as well as the lack of progression of brainstem atrophy on MRI should be checked regularly (at least once a year) after the treatment regimen is firmly established. Again, CSF IL-6 might be a useful surrogate marker for this purpose and should be examined once a year or more frequently if possible (27).

Discussion
The current studies have provided a guideline for the management of NB, including ANB and CPNB. It should be noted that the 2018 update of the EULAR recommendations for the management of Behçet's syndrome (Behçet's disease) described the recommended treatment of acute attacks of parenchymal involvement, which correspond to ANB attacks (9). This recommendation was basically the same as that in the present study, except for the effectiveness of colchicine in preventing the relapse of ANB attacks (15). However, while the EULAR recommendation supported the use of azathioprine for ANB (9), the present review did not recommend this. There have been no RCTs regarding colchicine or azathioprine for ANB. However, in a study with a retrospective analysis of 61 patients with ANB, the results demonstrated the efficacy of colchicine, but not azathioprine, in preventing relapse of ANB (15). Furthermore, in one study, azathioprine was less effective than cyclophosphamide in preventing relapse (16). Cyclophosphamide should not be given over a long period of time because of its carcinogenicity (24). Therefore, our recommendation appeared to be more convincing than the EULAR recommendation, although further studies are required to confirm this point.
The most important message in the current recommendations is the overarching algorithm for the clinical practice of NB, incorporating ANB and CPNB as independent clinical entities and clarifying their relationship. Although CPNB was described as chronic progressive nervous system involvement in the 2018 EULAR recommendation, no details were mentioned (9). The presence of the progressive subtype of NB has been noted for more than 20 years, not only in Japan (5) but also in Turkey (4,28). Furthermore, the first systematic review and meta-analysis confirmed the discrimination of ANB and CPNB as separate clinical entities (8). Although the frequency of CPNB is much lower than that of ANB, the recognition of CPNB is extremely important, since its treatment is totally different from that of ANB (3,7), with corticosteroids and conventional immunosuppressive drugs, such as azathioprine and cyclophosphamide, not being effective (7) while MTX and infliximab exert favorable effects (7,10).
It should be also noted that the diagnostic criteria for ANB and CPNB have been established based on the results of a retrospective survey of 144 patients (3). Special attention should be paid to the persistent elevation of CSF IL-6 over 17 pg/mL. Thus, a treat-to-target approach for CPNB also involves keeping the CSF IL-6 level below 17 pg/ mL (3). Although the measurement of CSF IL-6 is not yet covered by health insurance in most countries, it can be now performed easily using enzyme-linked immunosorbent assay kits at the lab bench for a relatively low cost. Therefore, as much effort as possible should be made to measure the CSF IL-6 level in clinical practice when encountering patients with possible or definite CPNB, as there are no alternative approaches available at present.
The limitation of these recommendations is that they were generated based on the results of uncontrolled evidence from open trials, retrospective cohort studies and expert opinions, thus resulting in relatively poor evidence levels for each CQ. In fact, there were no RCT results available, even for ANB (29). In addition, the current studies were not able to show how early CSF IL-6 levels should be reduced in patients with CPNB. Further studies are needed to address this point. By contrast, one strength of this study is that the task force in the present study included seven rheumatologists (one also with neurology board certification) and three neurologists. There was excellent concordance between the levels of agreement of the rheumatologists and those of the neurologists in all of the CQs, thus enhancing the reliability of the agreement levels on which recommendation levels were based in the present study.
In conclusion, we established 13 recommendations for ANB and CPNB. Although the frequency of CPNB is much lower than that of ANB, its recognition is very important due to its poor prognosis and differing treatment regimens from ANB. The international dissemination of these guidelines will facilitate the improvement of the management of patients with ANB and CPNB.

Financial Support
Supported by a grant for the Behçet's Disease Research Committee, the Ministry of Health, Labor and Welfare of the Japanese Government.