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From a JAK to a king of Castleman disease

DII small banner By Warren R. Heymann, MD
May 15, 2017

A 44-year-old Chinese woman with a 10-year history of asymptomatic cutaneous patches and plaques on her trunk (Fig 1, A) who reported intermittent fever and lymphadenopathy for 6 months. A skin biopsy specimen from a cutaneous plaque showed perivascular infiltration of plasma cells mixed with lymphocytes in the dermis (Fig 1, B). The histopathologic examination of a cervical lymph node supported the diagnosis of the plasma cell variant of Castleman Disease. 
Credit: JAAD

Throughout my career, I have been baffled by the concept of Castleman disease (CD). As a dermatologist, I am aware of its association with paraneoplastic pemphigus or POEMS syndrome, but I never quite had a handle on it, other than knowing that it is a rare, potentially fatal lymphoproliferative process. Although still an enigma, recent advances have shed light on the pathogenesis and treatment of CD.

According to Chan et al, CD comprises a heterogeneous cluster of disorders, characterized by lymphadenopathy with unique histological features and associated with cytokine-driven constitutional symptoms and biochemical disturbances. CD may be unicentric (UCD) or multicentric (MCD). “MCD may be subdivided by HHV-8 status, because all cases of HHV-8-related MCD appear to be a unified clinicopathological entity with consistent clinical features and outcomes, irrespective of HIV status. As all HIV-positive MCD cases are strongly associated with HHV-8 infection, the distinct phenomenon of HIV- and HHV-8-negative MCD has been termed “idiopathic MCD”, reflecting the paucity of knowledge regarding its pathophysiology. UCD is not typically associated with HIV or HHV-8 infection.” (1) CD is also categorized in terms of lymph node histopathology, with hyaline-vascular, plasmacytic, and mixed cellularity variants; a fourth variant, plasmablastic, is found only in MCD. (2)

The pathogenesis of CD focuses on the overproduction of IL-6 and VEGF. Excess IL-6 may occur via activation of the nuclear factor kappa B pathway as well as HHV-8 latency-associated nuclear antigen (LANA)-mediated upregulation of IL-6 transcription, which promotes the secretion of VEGF (vascular endothelial growth factor (1). Current theory suggests that the IL-6-mediated signaling cascade is initiated as two IL-6 molecules bind to either two membrane-bound IL-6Rs or two soluble IL-6Rs (sIL-6R). These complex with Janus Kinases (JAKs) leading to activation of JAK1. (3)

Therapeutically, UCD is curable with complete surgical excision, however, MCD is a therapeutic challenge. Treatment has focused on the use of cytotoxic agents [CHOP], other immunomodulators, rituximab, and antiviral agents such as valganciclovir.  Biologics, notably monoclonal antibodies to IL-6 and its receptor, allow for more targeted disease-specific intervention (1). The key biologics approved for CD are tociluzimab (Actmera) directed against the IL-6 receptor, and the IL-6 monoclonal antibody siltuximab (Sylvant). Siltuximab is indicated for idiopathic CD; its efficacy has not been addressed in HHV-8-driven disease (2).

Patel et al investigated and identified a molecular aberration(s) that helped explain the exceptional response to siltuximab in a patient with cutaneous CD. A woman in her 50’s was diagnosed with cutaneous CD. She was HHV-8 and HIV-negative. Her serum IL-6 was within normal limits. She had been unresponsive to rituximab, valacyclovir, azathioprine, hydroxychloroquine, minocycline, and steroids. She was treated with infusions of siltuximab — her skin lesions improved within 24 hours. She attained a complete response that was durable for 7 years, at which time she stopped therapy. Within a year of discontinuing the infusions, her CD recurred; infusions were reinstituted and she improved again.. Her tissue was sent for next-generation sequencing, allowing for comprehensive genomic profiling. The sequencing demonstrated a JAK1V310I missense mutation. Because Janus Kinase 1 (JAK1) is a crucial signaling component of the IL-6/IL-6 receptor/gp130 machinery, the authors concluded that the mutation induced a conformation change with a functional activation effect, leading to enhanced sensitivity to the IL-6 ligand. This could have explained the underlying biology of her cutaneous CD, and her exceptional response to siltuximab. (3)

This was a report of a mutation in the IL-6/IL-6R/gp130/JAK1/STAT signaling pathway in a solitary patient with CD. It remains to be determined if similar mutations are evident in other cases of CD. What is clear is that the understanding of the molecular machinery that drives CD is on the cusp of being elucidated, and the ability to manipulate it to therapeutic advantage is upon us.

1. Chan KL, et al. Update and new approaches in the treatment of Castleman disease. J Blood Med 2016; 7: 145-58.
2. Koff JL, Lonial S. Emerging treatments in Castleman disease – a critical appraisal of siltuximab. Biologics 206; 10: 9-15.
3. Patel M, et al. JAK2 genomic alteration associated with exceptional response to siltuximab in cutaneous Castleman disease. JAMA Dermatol 2017; 153: 449-52.

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