Reply to the Letter: ‘Thrombotic microangiopathy in adult-onset Still’s disease: the story is just beginning’

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Thrombotic microangiopathy in adult-onset Still’s disease: the story is just beginning

We would like to commend the Authors for their valuable Letter [1] concerning our review about the ‘Complications of adult-onset Still’s disease (AOSD) and their management’ [2], and to thank them for their relevant remarks regarding the section pertaining to thrombotic microangiopathy (TMA). We do embrace the criticism raised by our detractor. There are two matters of debate here, which, as of now, remain speculative.

First, the extreme rarity of both syndromes, adult onset still disease (AOSD) on the one hand, and idiopathic thrombotic microangiopathy (TMA) on the other hand, strongly suggests, indeed, a common pathophysiological link rather than a coincidence (it may be grossly calculated that the odds for such a coincidence would be around 10⁻¹¹). Nevertheless, that link has not been unraveled. While we were inspired by at least one case reporting a decreased ADAMTS13 activity (<10%) in the plasma sample obtained before the plasma-exchange treatment in a woman with a previous history of AOSD [3] and hence acted like if such patients should be considered – and treated – as if they were affected by thrombotic thrombocytopathic purpura (TTP), a number of cases with AOSD-related TMA but without severe (or not mentioned) ADAMTS13 deficiency have also been reported, as reminded by our detractors. Therefore, we take their point: we have too rapidly aligned AOSD-related TMA with TTP and we would urge physicians to perform an extensive (state of the art) exploration of TMA in new incident cases, not only including ADAMTS13 activity but also the sequencing of genes involved in the regulation of the alternate complement pathway to look for variants, for example. Nevertheless, we would like to stress out the following points: AOSD is listed as a disease associated with authentic autoimmune TTP cases [4]. Second, although the biological assessment of ADAMTS13 activity has a sensitivity close to 100% [5], it appears that the activity is occasionally measured only after the beginning of plasma exchanges. Last, every other adult (not child) patient with a genetic deficiency of ADAMTS13 and TTP has a low but detectable ADAMTS13 activity ex vivo, which is compelling enough [6]. We agree that we may not ascertain that AOSD-associated TMA is due to TTP per se, i.e. to an anti-ADAMTS13 antibody. To our knowledge, besides complement-mediated TMA in catastrophic antiphospholipid syndrome [7], only two other antibody-mediated forms of TMA are known today: the non-allelic homologous recombination of complement factor H related 1 (CFHR1) gene [8] which elicits antibodies against complement Factor H (not intuitively relevant here), and quinine-dependent TMA where antibodies are reactive to platelets and/or neutrophils [9]. The latter is more hypothesis-generating in the context of AOSD. In any case, the current trend is to consider this pathology being a systemic auto-inflammatory disorder rather than an autoimmune disease, and the existence of an increased leukocyte and neutrophil count (which is a cardinal symptom in AOSD) is intriguing [10].

Which brings us to the second and even more important question of how to treat patients with AOSD-related TMA. Here again, we embrace some of our detractor’s remarks. It might appear somehow artificial to write like we did that specific treatment of AOSD should only be contemplated after the treatment of TMA. However, this dichotomy in the way of presenting our therapeutic strategy was more chosen for pedagogical reasons, rather than a time-frame strategy to follow literally. Indeed, it seems important for us to emphasize that TMA is a serious and potentially lethal complication of AOSD, that should be managed in an intensive care unit, as supportive treatment is an emergency; ideally, when possible, therapeutic decisions should be taken in multidisciplinary rounds, with experts of TMA and AOSD (keeping in mind that owing to the rarity of both diseases, it is also very uncommon, if not exceptional, to find physicians who are truly experts of both pathologies at the same time and in the same place). We do agree with our detractors that rituximab and caplacizumab – a nanobody directed against vWF and preventing its link to platelets – are now considered as front line therapies in TTP. We haven’t mentioned the latter drug, but to our knowledge, there is no case of treatment with this therapy in an AOSD-related TMA reported in the literature to date. We also share our detractors view that vincristine is a quite outdated and questionably effective therapy [2], and that splenectomy should come afterward the aforementioned drugs; that is why we had clearly specified that it should be proposed as a last resort [2]. Finally, we share the thought that AOSD-directed biotherapies should be rapidly considered in front of a life-threatening complication of AOSD. Nevertheless, physicians should keep in mind that the risk of worsening an AOSD-related TMA when introducing too rapidly a biological drug exists in theory, and that data on successful use of biotherapies in this situation are scarce [11,12].

We hope that our point of view is now clearer, and thank our detractors for having permitted to clarify our thoughts. Realizing that some passages of our review might be misinterpreted, we would like to suggest an erratum in order to remove any ambiguity.

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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Funding

This paper was not funded.