We commend the authors of ‘Complications of adult-onset Still’s disease (AOSD) and their management’ [Citation1] for their remarkable review which explores some of the little-known facets of a rare and proteiform disease. However, we do wish to voice some remarks regarding the section pertaining to thrombotic microangiopathy (TMA).
First, TMA does not equate with thrombocytopenic thrombotic purpura (TTP). TMA encompasses an ever-growing myriad of heterogeneous conditions for which a common denominator is the existence of mechanical hemolytic anemia and thrombopenia. TTP is predominantly an autoimmune disease driven by anti-ADAMTS13 auto-antibodies (or less frequently due to congenital ADAMTS13 deficiency) and is only one among multiple other causes of TMA. Fine tuning the definition of TMA is an essential step as some of the following incorrect assertions derive from this initial erroneous assumption.
Many of the clinical reports connecting TTP to AOSD seem to be based on the outdated concept that patient with prominent neurological features should be categorized as TTP [Citation2], when in fact the diagnosis hinges on lowered levels of ADAMTS13, as rightfully noted by the authors themselves. Renal biopsy carried out in this population has repeatedly yielded histological features consistent with TMA. This is an uncharacteristic feature in TTP [Citation3] and, conversely, a defining criteria for the hemolytic and uremic syndrome (HUS), a different subcategory of TMA. These clinical aspects question the true relationship between AOSD and TMA and its adequate classification [Citation4–Citation7]. In fact, a careful review of the aforementioned reports reveals that ADAMTS13 levels are typically either normal or not reported as reviewed by Masuyama et al. 2013 [Citation2,Citation4,Citation5,Citation8–Citation12].
A steady stream of case reports have shown an impressive – albeit often transient – clinical improvement of TMA-associated pathological features following initiation of plasmapheresis [Citation6,Citation9,Citation13] with some authors hastily inferring that the underlying complication is related to TTP [Citation11,Citation14]. Although, these reports provide hints on a potential pathophysiological relationship between AOSD and TMA, as well as meaningful insights on possible therapeutic management of this dreaded complication, it should not be regarded as conclusive evidence for TTP. Besides being the mainstay for TTP management, plasmapheresis was also the chief therapeutic option in complement-mediated (atypical) hemolytic and uremic syndrome prior to the advent of eculizumab [Citation15]. It may thus be argued that the beneficial effect of plasmapheresis in AOSD associated TMA may well be mediated by its ability to thwart complement dysregulation [Citation7]. That said, these nosological considerations overlook the key issue which is the relationship between the state of inflammatory overdrive distinctive of AOSD on one hand and TMA on the other. None of the readily available data has produced meaningful pathophysiological hypotheses so far, with the exception of the report of El Karoui et al. The authors noted diminished glomerular VEGF expression in one case suggesting that IL-18 induced VEGF inhibition may have elicited TMA akin to anti-VEGF therapies [Citation6].
The misleading alignment of AOSD-induced TMA with TTP results in equally misleading therapeutic recommendations based on the management of TTP. Even if AOSD-induced TMA was, in fact, a genuine form of TTP, current therapeutic management of TTP differs from the therapies proposed by the authors. Rather than IVIG, cyclophosphamide or cyclosporine, rituximab and caplacizumab are preferred options; the authors failing to mention the latter [Citation16,Citation17]. In fact, rituximab and caplacizumab are now envisaged as front line therapies [Citation18,Citation19]. Bearing in mind all these aspects, should AOSD-directed biotherapies truly be considered ‘afterwards’? In other words, based on a debatable rationale connecting TTP with AOSD should perilous (splenectomy) or questionably effective therapies (vincristine) be given the priority over therapies targeting the root cause of TMA?
In conclusion, if there is strong clinical evidence suggesting that TMA should be deemed a potential devastating complication of AOSD, it is nonetheless unlikely that all cases universally fit the classic definition of TTP. The limited source of data (30 cases at best) as well as the absence of a sound pathophysiological rationale linking both diseases warrant further caution regarding any definitive classification of TMA in the setting of AOSD. Accordingly, clinicians should refrain from indiscriminate application of therapeutic recommendations issued for TTP.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
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