POEMS Syndrome

A new study confirms that idiopathic plasmacytic lymphadenopathy is an independent disease subtype of idiopathic multicentric Castleman disease. Idiopathic plasmacytic lymphadenopathy (IPL) is a clinical condition marked by an excessive amount of antibody production due to the proliferation of polyclonal plasma cells in the lymph nodes. At present, it is not clear if IPL is a subtype of idiopathic multicentric Castleman disease (iMCD)-not otherwise specified (NOS). In a new study, researchers from Okayama University have found clinicopathological evidence needed to establish a separate disease unit for IPL under iMCD-NOS. Multicentric Castleman disease (MCD) comprises a heterogenous group of rare disorders that exhibit generalized symptoms such as swelling of lymph nodes, anemia, fever, and fatigue. The causative factors underlying MCD include Kaposi sarcoma-associated herpesvirus (KSHV)/ human herpesvirus 8 (HHV8) infections. KSHV/HHV8-negative MCD without association with the POEMS (polyneuropathy, organomegaly, endocrinopathy, M proteins, and skin changes) syndrome are termed "idiopathic," i.e., diseases with no identifiable cause, and are thus referred to as "iMCD." At present, specific clinical manifestations or diagnostic criteria have not been identified for iMCD, which often results in treatment delay. iMCD is further classified as iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). With additional research efforts, iMCD-NOS, which is highly heterogenous, could be classified into various subtypes. Interestingly, a disease known as idiopathic plasmacytic lymphadenopathy (IPL), which is characterized by hypergammaglobulinemia, i.e., high levels of serum immunoglobulins, and histologically mature plasma cell proliferation in the lymph nodes, is considered a part of iMCD-NOS due to their clinicopathological similarity. However, till date, no study has validated if IPL has distinct clinicopathologic features compared to other iMCD-NOS. This motivated a team of researchers led by Assistant Professor Asami Nishikori, including Associate Professor Midori Filiz Nishimura, and Professor Yasuharu Sato from Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Japan to conduct a thorough clinicopathological examination of IPL and others in iMCD. Their findings were published on September 7, 2022, in the International Journal of Molecular Sciences. "We wanted to determine whether IPL has distinct and uniform clinicopathologic features compared to other subtypes (non-IPL) in iMCD-NOS," remarks Assist. Prof. Nishikori while discussing the motivation behind the study. The team analyzed lymph node specimens derived from 42 Japanese patients with lymph node involvement of iMCD-NOS, who met the consensus diagnostic criteria of iMCD and were negative for KSHV/HHV8 infections. Upon further examination, the team classified 34 of the 42 patients as the IPL group and the remaining 8 as the non-IPL group. On grading histological features such as vascularity, plasmacytosis (high proportion of plasma cells), atrophic and hyperplastic germinal centers (GCs), the team identified significant pathological differences between the specimens of the IPL and non-IPL groups. The IPL group demonstrated greater plasmacytosis and hyperplastic GCs compared to the non-IPL group. Conversely, the vascularity of the non-IPL group was higher than that of the IPL group. Clinically, the IPL group exhibited higher platelet count and serum antibody (immunoglobulin G) levels, with lesser fluid retention in pleural and/or abdominal cavity. The frequency of disease-specific autoantibody detection was also different between the groups. In addition, the clinical course and treatment responses in the two groups were also distinct. Upon treatment with tocilizumab, an anti-interleukin 6 receptor monoclonal antibody approved to treat iMCD in Japan, there was a significant improvement in the condition of patients with IPL. In contrast, patients with non-IPL responded poorly to the drug and showed progressed disease activity, requiring more intensive treatment. These findings were consistent with those of previous studies that suggest that the clinical course of IPL disease progression is slower as compared to the non-IPL group, and with a superior response to anti-IL-6 agents. Discussing these findings, Assist. Prof. Nishikori states "Given the heterogeneity of non-IPL cases, we must try to identify its primary cause. Molecular analysis could lead to a better understanding of disease pathology and the development of subsequent targeted therapies." To sum up, these findings have established IPL as a clinicopathologically uniform disease, which can be reclassified into an independent subtype of iMCD. So, what are the future implications of these findings? "It is critical that patients get the most out of any treatment modules. Studies on iMCD subtype-specific diagnostic biomarkers, treatment, and follow-up are thus warranted in the future to improve the clinical outcomes for these patients," concludes Assist. Prof. Nishikori.

In the EU, a disease is defined as rare if it affects no more than 1 in 2,000 people and similarly in the US it is defined as a condition that affects less than 200,000 people.1 Despite being referred to as ‘rare’, collectively, there are 6,000 to 8,000 known rare diseases2 and more than 300 million people around the world are living with one.3 For these people, living with a rare disease can mean a long wait to receive an accurate diagnosis, less options in terms of care, and many unanswered questions. In order to address this current unmet need, we must bring a new focus to the challenges faced by those with rare diseases. The challenges of a rare disease: Castleman disease One such rare disease is Castleman disease (CD) – a group of unusual and life-threatening lymphoproliferative disorders that affect the lymph nodes and related tissues.4,5 Multicentric Castleman disease (MCD) is one of two main subtypes of CD, along with Unicentric Castleman disease (UCD). UCD only affects a single group of lymph nodes, whereas MCD is systemic and affects multiple regions, such as the chest and abdomen. MCD can be further divided into three categories – human herpesvirus-8 (HHV-8) associated MCD, MCD associated with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome and idiopathic MCD (iMCD).5 iMCD affects lymph nodes and related tissues5 but unlike other subtypes of MCD, as the name suggests, the cause of the disease is relatively unknown. Approximately 540-960 people in the US are affected each year, with a similar number estimated in Europe5 but because of its many unknowns and the fact that it presents differently from other subtypes of the disease, iMCD patients have the worst prognosis among those diagnosed with CD.5 With so few cases presenting, physicians are often unfamiliar with iMCD and very few have first-hand experience of treating it, making it difficult for physicians to diagnose the condition confidently and accurately. It has only been since 2017 that diagnostic criteria to support the identification of iMCD has been in place.5 In fact, the disease was only brought into focus recently after Physician-Scientist, Dr David Fajgenbaum - whom himself fell ill with iMCD - penned his memoir “Chasing My Cure: A Doctors Race to Turn Hope into Action”. It is this book that is often attributed to putting the disease on the map, highlighting the unique research approach Dr Fajgenbaum took to identify the disease and unlock effective treatment options. He also established the Castleman Disease Collaborative Network (CDCN), as a way to accelerate research into CD and support better patient outcomes. A lot of resulting progress has been made, but more challenges remain. Beyond limited first-hand experience, iMCD is frequently misdiagnosed because symptoms are non-specific and overlap with several more well-known conditions such as human immunodeficiency viruses (HIV), rheumatoid arthritis and some blood cancers like lymphoma and multiple myeloma.5 These must first be ruled out,6 creating further diagnosis delays. For some, symptoms may include enlarged lymph nodes, weight loss, fatigue, and fever.7 In more severe cases, an uncontrolled release of pro-inflammatory cytokines, known as a cytokine storm, may occur. This, along with a subsequent overproduction of immune cells, can lead to organ failure.8 At this stage, it is often too late for intervention and historically, we have seen patients die within two and a half years of diagnosis and less than 30% surviving beyond five years from diagnosis9 – a mortality rate that is amongst or higher than those of progressive non-Hodgkin’s lymphoma, stage II colon cancer and stage III breast cancer.10 What’s more, it was observed in a retrospective analysis of US real-world data claims that within the first year of diagnosis, iMCD patients had a 49.6% increase in inpatient hospitalisations and a 32.8% increase in emergency room visits. Within one-year of diagnosis, 27% of patients experienced malignancy, 12% suffered from renal failure, and 6.8% were affected by respiratory failure or Thrombus.9 Early diagnosis is therefore essential to reducing mortality in iMCD patients.5 These challenges have often left both patients and physicians with more questions than answers. It is not surprising therefore, that the initial relief that may be felt for people with iMCD when hearing they do not have cancer, may be short-lived, and instead replaced by newfound anxiety. Finding a rainbow after the storm Recently, the concept of the ‘cytokine storm’ has risen to notoriety because of the part it has been suggested to play in the development of severe symptoms in a number of COVID-19 patients.11 During this time, we have seen the scientific community come together rapidly to put this phenomenon under the microscope, to understand the complex interplay of numerous factors in this process and thereby identifying and trialling several promising treatments. The uncertainty of COVID-19 brought with it a frightening new reality for all, but for many patients with a rare disease, worry and uncertainty is a reality that they live with daily. In just over a year, we have adapted and grown our knowledge of COVID-19 beyond expectation. Now that we have proven what is possible, and as we move towards vaccination and start to look forward with optimism, we must now take these learnings and translate them into the rare disease space. An enormous amount of positive progress has been made in little more than 12 months with COVID-19, a resounding demonstration of the power of collaboration and what can be achieved with focused research and development. We now need to apply these efforts to the rare disease space, to overcome the uncertainty that patients still face and better support early diagnosis and treatment. The future for rare disease This year’s Rare Disease Day focus – rare is many, rare is strong, rare is proud – highlights a growing sentiment in the rare disease community, that people with rare disease do not receive the equal opportunity for diagnosis and care they deserve. By harnessing the learnings of the pandemic around collaboration and commitment to research and understanding, we can support better outcomes for patients. We have seen through the COVID-19 pandemic what can be achieved through true collaboration, dedication, and commitment to research. Moving forward, we need to come together and apply this approach, not only to Castleman disease, but to all rare diseases. Around the world, important work is already being done to overcome the challenges faced by both patients and physicians alike, but we need to, and can, do more.