Adamantiades-Behcet's disease: From the first known descriptions to the era of the biologic agents

Abstract

In 1937, Dermatologist Hulusi Behcet presented a case of a patient with a 7-year history of recurrent ocular lesions, oral aphthous ulcers, and genital ulcers. The case report with the addition of a similar one was published in 1937.¹ Behcet published three more relevant papers most importantly pointing toward a single disease-syndrome from 1938 to 1940. In 1930, the Ophthalmologist Benedictos Adamantiades had described a case report of a disease with the title “A case of relapsing iritis with hypopyon.”² Interestingly, we find Adamantiades-Behcet's disease (ABD) descriptions not only from Hippocrates of Kos but also from clinical observations similar to ABD disease recorded from 1772 to 1940.^{3, 4}

Adamantiades-Behcet's disease (ABD) is a chronic, multisystem inflammatory disorder, which is clinically characterized mainly by relapsing oral aphthous, genital ulcers, ocular, and vascular lesions. The disease may affect small and large vessels in almost all organs. It is a rare disorder with the highest prevalence in the Eastern Mediterranean area and in Central and East Asia along the Silk Road. The exact etiology remains to be elucidated although environmental, genetic, and immunological factors are speculated. The current hypothesis is that of a probable autoimmune etiology vasculitis with no current pathognomonic test available.

The International criteria for Adamantiades-Behcet's disease (ICBD) include ocular lesions, oral aphthosis, and genital aphthosis each of these assigned 2 points, while skin lesions, central nervous system involvement, and vascular manifestations 1 point. The pathergy test accounts for 1 point. A patient scoring 4 or more points is classified as having ABD. The aforementioned criteria followed the existing International Study Group (ISG) criteria for the disease from 1990. Those required the presence of oral ulceration plus any two of genital ulceration, typical defined eye lesions, typical defined skin lesions, or a positive pathergy test. This description was considered to be of high specificity and low sensitivity. The Behcet disease current activity form, the oral ulcer composite index, or Mumcu et al. mucocutaneous activity index are in use for the management and treatment of patients.^{5, 6}

Moreover, male gender, early development, and HLA-B51 positivity are markers of severe prognosis. ABD is characterized mainly by elevated levels of Th1 and Th 17 cell-related cytokines coming from various sources. More specifically, IFN-γ, IL-2, and TNF-a can be detected in increased blood levels. Both innate (natural killer cells) and adaptive immunity are involved in the pathogenesis of the disease. Affected organs show increased infiltration by neutrophils and lymphocytes.⁷ Moreover, vascular inflammation, endothelial dysfunction, and angiogenesis may be partially responsible for the pathophysiology of ABD. Further to that overproduction of free reactive oxygen species ROS by neutrophils and the induction of extracellular DNA traps (Netosis) are involved in the inflammation mechanism. A highly interesting aspect of ABD is how immunosenescence can explain the fact that with advanced age there is lower disease activity. In particular, the immune changes on both innate and adaptive immunity with age, the chronic inflammation with the exhaustion of T lymphocytes, as well as age related hormonal changes are recently studied as a proposed pathophysiological mechanism in relation to the disease.^{7, 8}

Genetically, HLA-B51 conferred the main susceptibility for ABD, and has been identified to affect clinical phenotypes. HLA-B57 and HLA-A 03 are independent markers. Non-HLA loci have also been implicated such as EGR2, IRF8, and IL23.⁸

Diagnosis is based mainly on clinical presentation although it may take 2–15 years to establish it. A widely acceptable theory is that ABD encompasses an inflammatory reaction triggered by infectious agents such as herpes simplex virus (HSV)-1 or even autoantigens.⁷ Minor, major or herpetiform aphthous lesions are a hallmark on the clinical presentation. Based on the above isolated anaerobic strains of bacteria by Mioura et al., and Streptococcus mitis group on saliva samples and their heat shock proteins products have been studied in relation to the disease. Five different phenotypes of ABD have been described with different management approaches and prognosis each of them. Genital ulcers, musculoskeletal, ocular, vascular, gastrointestinal, pulmonary, and urogenital involvement are included on the broad spectrum of ABD. Finally, the pathergy test where the skin micro puncture promotes abnormal and increased cutaneous vascular infiltrate with cytokine release is considered highly diagnostic. A positive test is an at least 2 mm papule often with a central pustule.⁹

A high index of suspicion is needed in some cases to spot early the disease and to differentiate it from complex aphthous stomatitis, ankylosing spondylitis or even Crohn's disease due to similar symptomatology.^{9, 10}

ABD increases significantly the mortality and morbidity. Over a year period in 2017, a UK study of 1281 patients concluded that there was an increased risk of ischemic heart disease, venous thrombosis, and mortality compared with corresponding controls.¹¹ Furthermore, David et al. assessed data over a period between 1979 and 2016, from France patients. On this multiple cause of death analysis, they found an earlier mean age of death for ABD patients compared to the general population. Young patient's mortality was related mainly to cardiovascular disease. Older patient's mortality was more related to infectious disease.¹²

The treatment approach needs to be individualized, depending on the severity of disease. ABD has a chronic relapsing–remitting course with poorer prognosis on ocular, vascular, neurological and gastrointestinal involvement. In Table 1 special attention is given on pediatric ABD that is more related to genetic factors. Careful transition must be taken from pediatric to adult medicine for adolescents with ABD.

In particular, treatment approach can be different in patients where there is skin, mucosa, and joint involvement, where there is usually not permanent damage but deterioration of the quality of life to when there is eye, vascular, nervous, or gastrointestinal involvement where there is risk for serious damage and potentially fatal/death. In the first category, the treatment may aim to create a balance between how it can improve the quality of life of the patient taking into consideration of the adverse effects or side effects of the medications used. In the latter category, the treatment primarily aims to control the inflammation of the organs affected so that there is no loss of function due to the serious damage that may happen. More aggressive treatment may be necessary and careful follow-up of these patients, often with the use of immunosuppressive medicine. Thus, the treatments being used differentiate based on the systems involved and also change over the course of time as the disease's manifestations evolve.^{10, 13}

ABD is a disorder that may involve more than one organ system and a multidisciplinary team treatment plan is often necessary. It is worth mentioning how important may be the existence of reference centers for their experience in the disease. This is also related to the fact that ABD's geographical distribution is not uniform worldwide. As mentioned before, some areas have a higher prevalence than others.

Finally on the grounds of severe ABD, reduction or cessation of immunosuppressant or immunomodulation treatment can be considered only at least 2 years of remission, and only under expert advice.

In conclusion, Adamantiades-Behcet's disease (ABD) remains since the early descriptions a medical condition that can be challenging to manage, affecting multiple organs and body tissues.

So far corticosteroids, immune suppressive and immune modulatory agents have been the most effective.^{13, 15, 21}

In particular, a lot of attention has been given over the last few years on the role of inflammatory cytokines and factors that may be implicated to the disease. New immunomodulating and immunosuppressive treatments have been used effectively on a broad range of ABD's manifestations. An example of the above is the effective use of agents such as Mycophenolate mofetil and azathioprine that act by inhibiting the purine pathway and subsequently diminish cell proliferation. Recently, Mycophenolate mofetil has been studied on refractory cases of ABD uveitis and it proves to be an effective new alternative therapy when combined with a biologic agent. In addition to that it may also be an option for maintenance therapy.¹⁴ Moreover, Janus kinase inhibitors are for example a novel drug class, studied also for their therapeutic potential on ABD management.²²

Overall, new treatments exist that target Interleukin ligands or receptors, produce neutralization through soluble TNF molecules, modulate gene and immune system, stimulate mTNF (Membrane bound TNF), and lead to bidirectional signaling and apoptosis.^15-21 (see Table 2).

As such the family of biologic agents is being included in the therapeutic ladder for the disease. In total, Biologic agents are not only promising treatment agents for ABD but rather an established approach on severe, refractory, and hazardous complications of the syndrome. Further studies need to be conducted in this highly interesting field.

All authors contributed to the editorial conception and design. Material preparation, data collection and analysis were performed by Ellie Stefanadi, Georgios Dimitrakakis, Inetzi-Angeliki Dimitrakaki, Nikolaos Sakellariou, Sangeeta Punjabi and Christodoulos Steafanadis.

The authors have no conflicts of interest to declare.

This research has received no external funding.