Castleman's Disease: A Multifaceted Review

Castleman’s disease, a lymphoproliferative disorder, causes lymph node enlargement in various anatomical positions. As a result of the dysregulation in cytokine signaling, for instance IL-6 in the JAK/STAT pathway, CD is characterized by exaggerated immune activation and inflammation resulting in organomegaly. Although multiple studies have been conducted to understand more about the disease, there are still several knowledge gaps in the field such as understanding the possible connection between CD and giant CAAs and also considering TAFRO syndrome an entirely different disease or simply a variant of iMCD. In this paper, we review the classification and the diagnostic criteria of CD, cytokine networks and inflammatory pathways involved in the disease mechanism, viral associations with both HIV and HHV-8 and discuss alternative therapeutic pathways. Developing a thorough understanding of these aspects is crucial for accuracy in diagnosis and treatment planning for such a complex disease.

When Benjamin Castleman first reported Castleman Disease (CD) in 1954, he described it as localized mediastinal lymph node hyperplasia resembling thymoma (63). Although that description differs from the one used today "benign proliferative lymphoid hyperplasia", the focus on histopathologic features established a foundation that future researchers were able to build on and understand the differences between the types and subtypes as well as the subtype specific treatment options. (1,2). When the disease was first discovered it was believed to be one singular entity, then the first breakthrough was its division into two main types; UCD (unicentric) and MCD (multicentre) (1). When further studies were conducted, it was found that there are more histological classifications named hyaline-vascular and plasma cell variants, with the former being more common with UCD and the latter more common with MCD. One of the most important milestones reached was the discovery of the relationship between HHV-8 (human herpesvirus-8) and MCD. It was found that many patients, mainly immunocompromised patients, are likely to have HHV-8 co-infected MCD. This led researchers to the classification of MCD into HHV-8-associated MCD and iMCD (idiopathic). The discovery of iMCD also allowed for further development of the diagnosis and classifications. The latest discovery was TAFRO syndrome; unique clinical symptoms that appear specifically with iMCD (2). The subtypes do not appear equally in all populations; UCD is far more apparent with younger patients while MCD is more common with older patients. This difference in distribution provided guidance to create a more effective and accurate framework for the clinical trials, taking into account race, gender, ethnicity, age, and any other factor that may affect the distribution. (2). Although there have been significant breakthroughs in diagnosing the subtypes of CD, there are still some diagnostic disparities as diagnostic practices vary globally (3). The most prevalent example of this is the recognition of TAFRO syndrome in Japan compared to the HHV-8-associated MCD in areas where HIV is common. Thus, this among other factors resulted in a population specific disease patterns that results in affecting the global treatment standards as there is a lack of international disease classification code (4). CD is a rare disease and whose rarity combined with the numerous clinical symptoms it shows and how it overlaps easily with other diseases makes it very difficult to accurately diagnose and classify the disease. Its rarity also results in insufficient studies and research being done address the gaps present in its research. There are no known specific unique manifestations, features, or biomarkers that can be used as key for its diagnosis. The lack of knowledge hinders the development of evidence based treatment. This results in underdiagnoses and misclassifications as well as the creation of epidemiological gaps in research (4). Although there is a global registry for CD, it is markedly limited and the information on it is not enough. That is partially due to the aforementioned rarity of the disease, difficulty in diagnoses and lack of international disease classification code, as well as limited data coordination and collaborations. This affects our understanding of the disease and the outcomes of the treatments used in different regions around the world (5)

As mentioned earlier in the paper, further research is required in diagnosing and classifying the disease. Each type and subtype requires a different method of treatment, for example with UCD a surgical excision is done and the individual would achieve complete remission with no need for immunosuppression, justifying aggressive local treatment. However, that is not the case with MCD as the target would be the underlying cause rather than the hyperplasia itself, sometimes the target would be IL-6 and other times it would be one of the other pathways. Therefore, accurate diagnosis and classifying the disease to ensure the best outcome for the patient is crucial (6). The framework currently used incorporates clinical symptoms, histological features, and laboratory markers, this approach maximises the diagnostic accuracy (6). For instance, with iMCD the patient should meet both major and at least two minor criteria, as well as excluding diseases that may mimic iMCD. In addition to histological features, such as hyperplastic germinal centres, and lab markers, such as elevated CRP, the diagnosis is much more accurate and therefore a standard diagnostic pathway is created for CD (6,7). To highlight the importance of the histopathological features, they are the main method for defining the subtypes by detecting the signature features. However, sometimes histological features overlap, in which identification becomes essential. For instance, both UCD hyaline-vascular type and HHV8-associated MCD show regressed germinal centres, however, UCD also shows layering of mantle zone lymphocytes, while HHV8-associated MCD shows viral inclusions in plasma blasts (6,8). Imaging alone cannot diagnose, however, it is important for the differentiation between the subtypes. The use of PET and CT scans allows for distinguishing UCD in which the disease is solitary, from MCD, in which its more distributed as they show how distributed the disease is (7). They also reveal calcifications and if there is any involvement of other organs. Imaging allows for the distinguishing it from other diseases that mimic it and deciding whether to proceed with a surgical or medical intervention (7,9). Even though there is standardized guidelines that should be applied, they are not sufficient enough, so not all hospitals and centres will show the same results due to variations in the perception of the histology. This is all due to gaps in institutional diagnostic standards, and it affects how therapy is approached moving forward with the diagnosis. In order to address the gaps and reduce the diagnostic heterogeneity, molecular diagnostic tools are being developed to detect specific genetic mutations and biomarkers, such as PDGFRB N666S in unicentric CD and NCOA4 L261F in idiopathic multicentric CD. This development will also provide further insight about the pathways, specifically using transcriptomic and proteomics, and their details which will open doors for more targeted treatments to be created for each subtype and improve the accuracy of diagnoses and treatment decision making (11). TAFRO stands for thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly, and there has been some controversy regarding its classification. Some researchers argue that it is a subtype of iMCD as it shares enough histologic features with it. Meanwhile, other researchers argue that it should be considered an entirely independent entity due to the distinct features, clinical course, prognosis and response to treatment. This lack of unity continues to make it significantly more difficult for research and reaching a definitive answer about the treatments used (10). Understanding the classification criteria is crucial as it provides the foundation for comprehending the pathophysiological mechanisms that result in that heterogeneity.

The lymphoproliferative characteristics found in CD are mainly due to a dysregulation in cytokine signalling, for instance IL-6 in the JAK-STAT pathway. Normally, the suppressor for IL-6 (SOCS) would keep the cytokine balanced and controlled. However, in the case of Castleman Disease , there is a defect in the mechanism resulting in excessive immune activation and inflammation (12). Understanding the mechanism has allowed the development of targeted therapy in which the receptors or specific steps in the pathway are targeted. Detailed examination of the IL-6 in the JAK-STAT pathway reveals that heightened levels of IL-6 results in increased synthesis of acute phase proteins, B-cell proliferation, plasma cell differentiation, and systemic symptoms such as fever, malaise, and organomegaly. This shows that this pathway, in cases where IL-6 is elevated, is the central axis of the disease. Due to this fact, it led to the use of anti-IL-6 therapy; IL-6 specific treatments in which the cytokine itself or its receptor are targeted, examples include tocilizumab and siltuximab (13). As effective as this treatment option is, it cannot be applied universally with all CD patients. It would be significantly more effective with iMCD than with HHV-8-associated MCD due to the fact that the latter releases vIL-6 (viral IL-6) which does not follow the same pathway as the endogenous IL-6 (13). It also releases Flip, which functions by activating the NF-kB pathway. As well as releasing cyclin, which acts by mimicking the body’s cyclins resulting in cell cycle progression, therefore supporting cellular proliferation and oncogenic transformation. Therefore, the normal regulatory mechanisms of the body do not affect it and it activates gp130 regardless of the receptor’s state. These mechanisms showcases exactly why anti-IL-6, although effective, will not be effective in all cases and in this specific case, the required therapy would be antiviral and targeting steps in viral replication (13,14,16). NF-kB is a protein complex involved in the regulation of immune and inflammatory responses in the body by controlling the expression of the genes regulating it. When upregulated, it causes an increased expression of multiple pro-inflammatory cytokines such as IL-1β and TNF-α, which promote further inflammation as well as activating survival signals in plasma cells, contributing to their proliferation and persistence. Therefore, this protein can also be used in targeted therapy as it allows for targeting multiple pathways (15). The relationships and hierarchy between cytokines are not fully understood. Targeting one cytokine may affect the pathway of another and vice-versa, therefore this creates a challenge when deciding the appropriate therapy; meaning that while theoretically a therapy might work, clinically it may have negative effects due to the complex interactions between the cytokines and inflammatory mediators (18). Furthermore, the gap concerning biomarkers and molecular profiling as a whole regarding Castleman Disease still remains. The lack of valid cytokine signatures and biomarkers make it extremely difficult to tailor the treatment according to the patients’ needs as their response to the treatment may be unpredictable. So even though many pathways have been discovered, the choices regarding what therapy to use are still considerably limited (19). To overcome the aforementioned issues, systems biology fuses various large-scale biological data (transcriptomic, proteomics, and metabolomics) and are likely to grant the opportunity to map the complex cytokine network, as well as understand the signalling mechanisms and interactions between them that cause the pathology of the disease. An approach like this would open doors to far more therapeutic options beyond IL-6 targeted therapy (20).

In some cases of Castleman Disease, and particularly MCD, there may be a viral co-infection. HHV-8 and HIV influence the disease’s pathology, patterns and dysfunctions, to the point of causing different progresses and presentation. This results in the different subtypes of MCD. Understanding their aetiology allows researchers to accurately classify the case, as well as focus more on finding therapies that would target the virus or its causes (14). The presence of HHV-8 and HIV pose an extremely high threat to the patient. HIV will worsen the immune system by targeting the CD4+ T-cells and resulting in their depletion. Simultaneously, it causes the reactivation of HHV-8 which increases the amount of cytokines released. Therefore, the inflammation and overall pathology occurs more severely in addition to immunosuppression and heightened inflammation. This dual effect of the viruses’ underlines why it is important to use combined therapy; antiretroviral therapy for HIV and antivirals to suppress HHV-8 (22). However, treating HIV in HHV-8 co-infected patients presents challenges. Antiretroviral therapy (ART) administration to treat HIV results in IRIS; immune reconstitution inflammatory syndrome is a phenomenon that occurs in which the increase in CD4+ T-cells and immune system recovery results in the worsening of inflammation and condition due to HHV-8(14,17). Therefore, managing antiviral therapy and monitoring the patient are extremely important steps to ensure the phenomenon does not become uncontrollable. However, with proper management and clinical observation of the patient, the immune system can recover properly while also minimizing the worsening of inflammation (21). HHV-8 and HIV are not the only viruses related to the disease. There are many others that have not been sufficiently researched; those include Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), and other herpesviruses. The lack of research creates gaps that may cause clinicians and researchers to ignore other therapeutic targets that may help, this can be especially the case with HHV-8 negative MCD patients. Understanding the roles of those other viruses and how they affect the immune system will help researchers comprehend the mechanisms of the disease more thoroughly (24). There is a substantial lack of evidence in regards to optimal antiviral therapies for CD. In order for a treatment to be effective, the viral load and types must be known and understood. However, in the case of virus associated CD no standard method currently exists for monitoring the load and guiding personalized antiviral treatment. Therefore, clinicians are forced to rely on empirical or trial and error approaches even though the heterogeneity of the disease is well known (21). Currently, the previous issue is being addressed by the rise of personalised virus associated CD treatment. The combination of viral genotyping, load monitoring, and host immune profiling (how well a patient’s body responds to the virus) allows for far more specific clinical decisions regarding the timing, duration and type of therapy a patient receives. All these factors positively affect the efficiency of treatment and management of the disease while also reducing the unnecessary use of other medication. The overall patient care and satisfaction will be improved significantly (26).

While the lymphoproliferative manifestations are the most apparent, they are not the only characteristic of CD. Recent reports have shown that multiple organs can be affected by CD in patients, such as the heart, resulting in cardiovascular complications, and the nervous system, causing neurological complications. Therefore, it is not accurate to simply say the disease affects the lymph nodes alone, as these reports prove that it can be wide spread and significantly affect other organs, making it a systemic disease. Therefore, when monitoring CD, all other possibly affected organs must be examined and monitored as well (52) A significant knowledge gap exists regarding the relationship between CD and coronary artery aneurysms (CAA). There have been cases reported in which the patients develop large and possibly harmful aneurysms in the coronary arteries. However, there is insufficient research studies about the topic. These aneurysms show high morbidity and mortality risk if not treated rapidly and effectively. Therefore, gaining a proper understanding of the link between the two is urgent and crucial so that the complication is diagnosed early and an intervention occurs at the optimal time (48) , (49). Regarding the neurological manifestations, they affect both the central and peripheral nervous systems. Several cases show these complications as well and further clarify the fact that CD is a systemic disease rather than a strictly lymph node proliferation. These cases highlight the importance of neurological screening during the management of CD to ensure detecting such complications as early as possible (51) The inflammatory cytokine cascade, which includes IL-6, TNF-α, VEGF, interferon, and many more play a crucial role in the development of cardiovascular complications. They promote abnormalities such as the aneurysms, and neural complications by directly affecting the tissues of each system; vascular endothelium and neural tissues. The complex interaction and network between the cytokines creates the inflammation and disease manifestation as well as the systemic symptoms. Knowing this information, it is highly probable that the systemic complications are directly due to these cytokines, however further research is required to prove this probability (50). It remains unclear whether the relationship between CD and the complications is accidental or causative due to limited case reports and studies with concrete evidence that CD activities causes these complications. Due to all these limitations and lack of assurance, often times clinicians find themselves overwhelmed and unable to choose the correct type of targeted treatment and whether or not the CD has anything to do with the other complications (54). Furthermore, there are possibly other extremely rare complications as well. However, due to the lack of a proper system that collects and compares data of these rare cases there is a gap in the topic and it is notably difficult to precisely observe how often the rarer complications occur or their causative factors. Additionally, the lack of data halters the development of evidence based methods of early detection and proper treatment, prevention, and there is no standard screening protocol and so each centre identifies and monitor complications differently (55). To further understand the complications and the disease’s pathway, it is essential to comprehend the pathophysiology of said complications and to achieve that there must be collaboration among researchers. Fusing cardiovascular imaging, neurological assessments, and inflammatory biomarker studies will explain how the various organs are affected and the role the inflammatory system plays. Once all that is understood, better tailored and targeted treatment can be developed eventually to treat and prevent these rare complications from occurring (53)

As previously discussed, UCD was a type of CD entirely different than MCD and considered the curable type. With the latter, a surgical approach, in which the affected lymph node is removed, would be out of the question due to the various locations. However, with UCD it is the automatic approach as it is highly successful with rare recurrence and a 5-year survival rate in over 95% of cases making it the gold standard and first-line treatment for UCD and highlights the importance of an early diagnosis (27). Although it is the gold standard, there are cases where the surgery would not be feasible. If the affected lymph node is in an anatomically difficult position such as near vital organs, blood vessels or nerves that would get affected during the surgery, clinicians use radiotherapy. Beam radiation at doses between 20-40 Gy was shown to allow local control of the disease in a way that is comparable to the surgery without the risks. By offering this control, radiotherapy becomes another curative option that broadens the horizon of available treatments In addition to traditional radiotherapy, there are more modern Radiotherapeutic treatments such as stereotactic body radiation therapy (SBRT) and intensity-modulated radiation therapy (IMRT). The main differences are the preciseness and ability to increase the radiation safely. In traditional radiotherapy, one specific uniform dose over several sessions without an extreme concentration on the target (23). Meanwhile, SBRT and IMRT take advantage of imaging, computer planning, and delivery techniques to coordinate the dose with the size and shape of the affected areas. In this way, efficiency and dose is safely increased and the side effects that may occur with traditional are avoided, such as destruction of the surrounding tissue. (23) There is an ongoing debate regarding the extent of the excision that should be made when removing the lymph node during surgery. Some professionals state that it is safer to remove the entire affected area to prevent the recurrence of the disease (27). However, others believe that the risk is extreme and the excision should be partial and only remove the proximal diseased areas. The complete excision approach would present a higher risk if the affected area is anatomically difficult to reach. Another risk could be the instances where the spread is borderline or unknown, therefore a clear margin cannot be made. In those cases, the latter is the safest option. The conflict appears due to the fact that optimal extent of tissue removal has yet to be defined and therefore each institution performs using a different surgical technique. The lack of agreement hinders the development of standardized protocols that optimize the patient’s prognosis (28) As effective as the open surgery is with UCD, there are still risks and side effects that also include perioperative complications. Therefore, VATS (Video-assisted thoracoscopic surgery) were developed and are currently used as a standard minimally invasive surgical technique. It is another surgical approach that is just as effective while also decreasing the risks and side effects that may occur with a typical open surgery. That is due to the smaller incisions, higher visualization, and precision of the instruments used as the openings are significantly smaller. This results in fewer perioperative complications, shorter hospital visits, and an easier recovery, as well as prioritizing the safety and improved quality of life all while not compromising the efficiency of the treatment (25)

While UCD is localised and curable by surgery, this approach is not applicable to MCD. As the name suggests, MCD is wide spread and more difficult to treat due to the mechanism of the disease. The issue stems from the overall dysregulation of cytokines, that results in widespread inflammation, organ dysfunction, and systemic symptoms, thus the simple removal of the affected node is not sufficient. Therefore, the most appropriate course of action would be administering anti-IL6 treatment as they target the inflammatory process in itself (30). Siltuximab is the first line treatment used with MCD where there is IL-6 dysregulation due to its ability in inhibiting IL-6 by directly binding to the cytokine and preventing receptor activation. Evidence shows that about 34% of people treated with it in clinical trials show durable responses; long term relief from any symptoms and prevention of relapse and no lab abnormalities proving that the drug is particularly efficient in controlling the disease and remarkably capable of targeting IL-6. However, it is not universally effective as there are some cases of resistance and lack of response (29) ,(40). Another drug used is tocilizumab. Similar to siltuximab, it also prevents IL-6 signalling, however it functions by blocking the receptor in itself and preventing the binding and remains just as effective. Due to this difference, tocilizumab can be a viable alternative option for treatment and sometime shifting between them may overcome resistance or inadequate responses to treatment (31) Even though siltuximab is extremely effective, there are still some challenges that face clinicians when using it. The main issue roots in the lack of viable biomarkers and indicators for the disease. This makes it very difficult to manage the disease and follow up with the patient, as well as indicate whether or not the patient will respond to the treatment which is called response prediction. Additionally, after they are given the treatment it is still difficult to identify the non-responders (19). Furthermore, the lack of consensus on how the doses should be adjusted makes it difficult for practitioners to know when to increase, decrease, or maintain the dose as is to prevent resistance and maximize the response. All these factors result in the treatment gap in CD research, as not all patients respond to Siltuximab. Thus, to bridge this gap further research is required to identify the biomarkers for response prediction and develop evidence based protocols to direct therapy adjustments (24). About 66% of CD patients either do not respond to siltuximab or the results are not sustained for long and their choices for treatment are very limited. This reveals that the majority of patients do not have their needs met, and in order to fix that problem alternative treatments are under development. Since targeting IL-6 does not work, other therapeutic methods that can be developed include other cytokines, immune pathways, or even cellular targets, as well as combining different therapies to provide the best outcome (19) Combining different therapies to target multiple inflammatory pathways simultaneously may demonstrate Preliminary efficacy. There have been clinical finding that suggest combining siltuximab with other agents improve the results with nonresponsive patients. Some specific combination strategies include Anti-CD20 therapy (e.g., rituximab); targets B-cells which are responsible for the antibodies released in CD. JAK inhibitors; block the JAK STAT pathways resulting in the inhibition of cytokines including IL-6 among others as well. Proteasome inhibitors; inhibits the NF-kB pathways and decreases the survival of plasma cells. (33) Novel IL-6 pathway modulators are new innovative therapeutic agents that target and regulate the IL-6 pathway and are meant to be more effective due to the comprehensive disruption of the IL-6 pathway signalling cascade and reducing resistance that occurs following monoclonal antibody therapy (24). It is composed of different classes. Bispecific antibodies; those antibodies target two molecules in one singular pathways which makes it more effective in treatment. Small molecule JAK inhibitors; as the name suggests, they inhibit the JAK1/2 which are mediators for IL-6 signal transmission by penetrating the cells and thus inhibiting the inflammation. Downstream STAT3 inhibitors; once JAK is activated they also activate STAT3 which is responsible for the expression of many genes involved in inflammation, immune response, and cell proliferation, therefore when blocked inflammation is inhibited. (34).

TAFRO syndrome is a systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (5). There is an ongoing controversy on whether or not TAFRO is considered a variant of iMCD or an entirely different entity. From a strictly clinical point of view, TAFRO is an entirely different entity due to the unique collection of symptoms separating it from classic iMCD. The distinctive symptoms indicate that it requires specific diagnostic steps and management as well as distinct treatment protocols (41) , (42). As stated, it seems as though TAFRO is far more common in Japan and east Asia than in the west where it is under recognised. This difference in geographical distribution indicates that there may be some geographical factors that affect the prevalence of the disease. These factors may be genetic, environmental, or enhanced clinical recognition about the disease and improved protocol to diagnose and manage the disease (4). The patient may be diagnosed using different clinical, histopathological, and laboratory parameters which causes the variation in categorisation of the cases. These variations make it difficult to collect data and compare the findings globally, as well as conducting proper reliable research about TAFRO. Furthermore, it stagnates the development of a global standardized protocol for diagnoses and treatment. Thus due to this inadequate amount of information it is crucial that more research is done on the topic (46). Furthermore, treatment response is variable especially to IL-6 inhibition. In some cases, it is enough while in other combination therapy is required, such as corticosteroids or other immunosuppressant’s. The variability and need for immunosuppression indicates that there is a difference in mechanism from iMCD; all of which uphold the point of view that TAFRO is a separate entity that requires personalized treatment rather than following the standard treatment for iMCD (47). The gaps in understanding the genetic signatures, biomarkers, and details of pathways in CD and contribute to the difficulty in differentiation between the TAFRO and iMCD. Thus, there is no choice but to rely on the clinical histological findings, however they will vary and may overlap with other diseases. Addressing these gaps is crucial so that the classification criteria is defined clearly and to overcome the disagreements (45) However, addressing the gaps is not enough. In order for the most proper and effective guidelines to be created proper global coordination is essential. Information must be collected globally, and collaborative studies involving multiple centres are needed to fully comprehend the molecular markers and pathways unique to TAFRO syndrome. With such collaboration, the pre-existing controversies surrounding TAFRO would be resolved and evidence based criteria and protocols would be developed (43) , (44).

Multiple additional cytokines are involved in CD pathogenesis, including IL-1. Blocking this cytokine using an antagonist can manage inflammation in ways that complement the inhibition of IL-6. Medications that utilize this mechanism include anakinra and canakinumab, they specifically antagonise IL-1β and have a wider effect in decreasing inflammatory activity and have been deemed successful in patients nonresponsive to IL-6 targeted methods. Therefore, medications using this mechanism may be used as second line of treatment (32) Additionally, plasma cell targeting demonstrates high efficacy as they are the source of the antibodies and inflammation in iMCD. In order to achieve this, proteasome inhibitors such as bortezomib are used. Clinical case series have shown the administration of bortezomib induces apoptosis in said plasma cells and therefore inhibit the NF-kB pathway and reducing inflammation and cell survival. The effects of this method are long lasting and provides hope that it may also be used as second line therapy (35) Another drug that targets B-cells is rituximab. Rituximab is an anti CD20 antibody and therefore decreases the amount of B-cells present. This results in less cellular sources for the pathogenic antibodies and is efficient whether it is used alone or in combination with another drug. Rituximab coordinates effectively with cytokine inhibition as this combination targets both the source of the antibodies as well as the pathway itself (36) Although numerous therapeutic options exist, there is still a limited number of clinical trials especially randomized controlled trials (RCTs) when it comes to alternative treatment. RCTs are high quality studies that give concrete evidence about the studied topic, without them researchers and clinicians depend on case series and reports to decide the treatment that should be used. While useful, they are not the most specific or dependable source of information, and it makes it more difficult to develop a global systematic standard of what should be treatments to use and when to combine therapies (37,38). The integration of precision medicine into iMCD would significantly improve the outcome of the patients due to the customization of the treatment for each individual. It would be a blend of molecular profiling (in which the patient's genes, proteomic and metabolic information are checked), pathway activity signatures (recognising which inflammatory or cellular pathways are active), and pharmacogenomics markers (understanding the patient’s genetic makeup and how it will affect the response to the treatment of choice). All these factors fused together will result in a well thought out, precise treatment plan specialised for each patient which will be far more effective with less side effects and unnecessary use of drugs with iMCD (39,33)

The shift from symptomatic treatment to precision medicine has occurred due to the advancements in molecular medicine. Targeting the underlying cause of the disease and understanding the pathophysiology as well as the molecular and genetic factors rather than just treating the symptoms is significantly more effective. Clinicians can diagnose much more accurately and effectively as well as personalize the treatment according to that individual’s exact needs (56) There are several molecular subtypes of CD. These subtypes were identified through the advancement of multi-omics profiling techniques, such as genomics, proteomics, and cytokine analysis. These methods provide the detailed molecular information that resulted in the discovery of the heterogeneity and diversity of CD, all of which also aid in deciding the personalized treatment plan for the patient (19) , (24) Additionally, molecular profiling is important for the development of biomarkers for CD. While some have been discovered, such as specific cytokine signatures, genetic markers, and protein expression patterns, non are standardised and the majority of the others are currently in the research and discovery phases (57). However, their discovery would allow clinicians to detect the disease a lot sooner as well as aid in predicting and monitoring the prognosis. Furthermore, determining biomarkers would be another factor that aids higher diagnostic accuracy, and in the personalization of the treatment and targeted therapy (19) Many obstacles still stand in the way of biomarker usage. The lack of union and consensus regarding protocol and criteria halters the comparison of results and studies. The reason as to why they are not used routinely is simply because they have not been tested thoroughly enough and in a diverse population to ensure they are truly accurate and reliable and would fulfil the theoretical expectations. Due to these complications, the transition from paper to clinical practice has been extremely difficult and standardization and validated studies are now an urgent need so that the latest molecular profiling advancements can be utilized (61) , (62) Although from a technological and educational stand point there have been incredible advancements in multi-omics approaches, integration gaps still remain; the theoretical information is known but cannot be properly practically applied. Moreover, they block clinicians from properly utilizing the details of molecular data to inform diagnosis, prognostication, or personalized treatment strategies. They result in the inability to translate all the known information into practical clinical care due to the lack of standardization, data complexity, and many more reasons. There must also be development of user-friendly, validated tools fused with actionable insights for everyday clinical decision making (58) , (59). Since one of the reasons for the integration gap is the data complexity and inability to convert it into actionable insights, there have been some interesting developments regarding AI. AI-driven analysis platforms convert the complex data into practical personalized treatment and actionable insights. They analyse data and patterns and conclude predictions much faster and more effectively than humans allowing the clinicians to immediately focus on helping the patient. This AI advancement can bridge the gap easily and perfectly once perfected (60)

Significant advances have been made regarding the classification, diagnosis, and therapies for CD all of which highlighted the complexity and heterogeneity. The gaps in diagnosis, classification, therapeutic approaches, and mechanisms were discussed. Additionally, AI-driven approaches demonstrate potential for addressing the integration gaps. Furthermore, the standardization of diagnostic protocols and criteria is extremely urgent and important so that centres and researchers worldwide can coordinate and compare results accurately and to also understand rare complications more thoroughly, as well as to resolve the ongoing controversies surrounding TAFRO. Overall, the integration of multidisciplinary research, novel biomarkers, and international collaboration will be the most critical moment in CD management history. It will be transformed from empirical to precision medicine and personalised treatment to each patient.