IgG4-related disease and Rosai-Dorfman-Destombes disease ...

Correspondence

show increased IgG4-positive plasma cells in lymph nodes and other tissues, sometimes accompanied by elevated serum IgG4 concentrations. Notably, some patients with Erdheim-Chester disease and rare inflammatory conditions, such as multicentric Castleman disease and eosinophilic granulomatosis with polyangiitis, also show increased IgG4-positive plasma cells in tissue and elevated serum IgG4.2,3 Rarely, tissue infiltration of IgG4-positive plasma cells exceeding the thresholds established for diagnosis of IgG4-RD (eg, >100 cells per high-powered field in lymph nodes with an IgG4positive to IgG-positive plasma cell ratio >40%) have been reported in RDD and Erdheim-Chester disease but, in general, the number of IgG4positive cells in these conditions do not meet the criteria for diagnosing IgG4-RD.4 Beyond the abundance of IgG4-positive plasma cells, other histological features can help to differentiate IgG4-RD from histiocyte disorders. Storiform fibrosis is present in nearly all cases of IgG4RD, but is rarely seen in RDD, whereas emperipolesis of plasma cells and lymphocytes penetrating through large S100-positive histiocytes is common in RDD but not present in IgG4-RD.

Polyclonal hypergammaglobulinaemia can often be seen in histiocyte disorders, but the serum IgG4 concentration rarely exceeds 5 g/L.5 As Emile and colleagues eloquently showed, RDD is a disease of clonal histiocytes, whereas IgG4-RD is driven by immune dysregulation involving CD4positive T cells and plasmablasts. Perhaps most importantly, treatment of RDD and IgG4-RD is quite different. RDD rarely responds to corticosteroid or rituximab monotherapy, whereas response rates for IgG4-RD are well above 90% for both these interventions. Keeping the boundaries between histiocyte disorders and other

rare diseases such as IgG4-RD is crucial, even as the areas of overlap present opportunities for better understanding of both diseases.

We declare no competing interests.

*Luke Y C Chen, Graham W Slack, Mollie N Carruthers

lchen2@bccancer.bc.ca

Division of Hematology, Department of Medicine (LYCC) and Department of Pathology and Laboratory Medicine (GWS), University of British Columbia, Vancouver, BC V5Z1M9, Canada; Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada (GWS); Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada (MNC)

1 Emile J-F, Cohen-Aubart F, Collin M, et al. Histiocytosis. Lancet 2021; 398: 157?70.

2 Chen LYC, Mattman A, Seidman MA, Carruthers MN. IgG4-related disease: what a hematologist needs to know. Haematologica 2019; 104: 444?55.

3 Gianfreda D, Musetti C, Nicastro M, et al. Erdheim-Chester Disease as a mimic of IgG4related disease: a case report and a review of a single-center cohort. Medicine (Baltimore) 2016; 95: e3625.

4 Liu L, Perry AM, Cao W, et al. Relationship between Rosai-Dorfman disease and IgG4related disease: study of 32 cases. Am J Clin Pathol 2013; 140: 395?402.

5 Zhao EJ, Cheng CV, Mattman A, Chen LYC. Polyclonal hypergammaglobulinaemia: assessment, clinical interpretation, and management. Lancet Haematol 2021; 8: e365?75.

Authors' reply

We thank Luke Y C Chen and colleagues for their comments on our Seminar.1 We acknowledge that IgG4-related disease (IgG4RD) is the correct name rather than hyper-IgG4 syndrome; however, we did not mean Rosai-DorfmanDestombes disease (RDD) is a subtype of IgG4-RD, or vice versa. The differential diagnosis between these two disorders is often challenging. Although some clinical features can help to distinguish between the two diseases (eg, skin lesions in RDD; tubulointerstitial nephritis in IgG4-RD),2,3 others definitely overlap. As also pointed out by Chen and colleagues, lymphadenopathy and pachymeningitis are common in both conditions and, if they are the sole disease manifestations and there is no

suggestion of a multisystemic clinical picture, the diagnosis can only be histological.

Histology poses additional challenges: hallmark features such as emperipolesis might not be abundant in RDD biopsies; like wise, obliterative phlebitis and storiform fibrosis might not be found in IgG4-RD (particularly in lymphadenopathy). In a series of 75 patients with RDD referred since 2016 to the French pathology centre for systematic or difficult histological diagnostic of histiocytosis, 33 (44%) of 75 had at least one high-power field area with a high IgG4 density according to Deshpande and colleagues.4 Furthermore, among the 23 patients reviewed with pachymeningitis related to meningeal RDD, some patients were initially diagnosed and treated as IgG4-RD, then subsequently referred to the French histiocytosis pathology centre because of resistance to treatment. Thus, a high IgG4positive plasma cell density does not help in the differential diagnosis, and histiocytes might also abundantly infiltrate IgG4-RD lesions.5 Notably, extranodal RDD lesions are usually associated with more fibrosis and less emperipolesis compared with nodal lesions, a histological picture that is closer to that of IgG4-RD.2

Molecular analysis of the lesional tissue can point towards the diagnosis of RDD (rather than IgG4-RD) if disease-related somatic mutations (eg, KRAS, NRAS, MAP2K1) are found. However, such mutations are only detected in fewer than 50% of RDD cases. Finally, RDD can overlap with Erdheim-Chester disease,6 which is (as Chen and colleagues acknowledge) a classic mimic of IgG4-RD.

To conclude, although we believe that in most cases RDD and IgG4RD are distinct conditions, the differential diagnosis between the two can be particularly challenging, even after an accurate analysis

1214

Vol 398 October 2, 2021

Correspondence

of their clinical, histological, and molecular features.

FC-A and JH are investigators (FC-A being the principal investigator) of an academic study on the efficacy of cobimetinib for treating histiocytoses (COBRAH, NCT 04007848). All other authors declare no competing interests.

*Jean-Fran?ois Emile, Augusto Vaglio, Fleur Cohen-Aubart, Julien Haroche

jean-francois.emile@uvsq.fr

EA4340 BECCOH, Versailles SQY University, Pathology Department, Ambroise Par? Hospital, AP-HP, Boulogne 92104, France (J-FE); Nephrology and Dialysis Unit, Meyer Children's Hospital, Florence, Italy (AV); Department of Biomedical, Experimental and Clinical Sciences Mario Serio, University of Florence, Italy (AV); Internal Medicine, Department 2, French National Referral Center for Rare Systemic Diseases and Histiocytoses, Piti?-Salp?tri?re Hospital, AP-HP and Sorbonne Universit?, Paris, France (FC-A, JH)

1 Emile J-F, Cohen-Aubart F, Collin M, et al. Histiocytosis. Lancet 2021; 398: 157?70.

2 Abla O, Jacobsen E, Picarsic J, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-DorfmanDestombes disease. Blood 2018; 131: 2877?90.

3 Maritati F, Peyronel F, Vaglio A. IgG4-related disease: a clinical perspective. Rheumatology (Oxford) 2020; 59 (suppl 3): iii123?31.

4 Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012; 25: 1181?92.

5 Corradi D, Maestri R, Palmisano A, et al. Idiopathic retroperitoneal fibrosis: clinicopathologic features and differential diagnosis. Kidney Int 2007; 72: 742?53.

6 Razanamahery J, Diamond EL, Cohen-Aubart F, et al. Erdheim-Chester disease with concomitant Rosai-Dorfman lesions: a distinct entity mainly driven by MAP2K1. Haematologica 2020; 105: e5?8.

The AKIKI 2 trial: a case

for strategy of initiation

instead of timing

I read with interest the AKIKI 2 trial by St?phane Gaudry and colleagues,1 which reiterates the strategy of watchful waiting for the initiation of dialysis in patients with acute kidney injury (AKI). I wish to bring forth two important aspects of the study design that can help to put the results of this important trial in context.

First, the definition of early or delayed initiation of dialysis, which

was based on the prespecified level of azotaemia or duration of AKI (as defined in the trial by blood urea nitrogen >112 mg/dL or oliguria >72 h), did not take into account the important observation that the AKI complications considered to be the absolute indications to start renal replacement therapy (RRT)--ie, hyperkalaemia, severe acidosis, fluid overload, pericarditis, and encephalopathy--do not necessarily correlate with the degree of azotaemia or duration of oliguria in a linear fashion. For example, uraemic bleeding2 or encephalopathy3 has no correlation with the degree of azotaemia. Therefore, a more pragmatic approach would be to decide when to initiate RRT on the basis of the presence or absence of these absolute indications, which can be considered as a prophylactic dialysis strategy or a so-called dialysiswhenever-indicated strategy.

Second, assessment of the primary outcome in the AKIKI 2 trial involved a clinician's judgement to discontinue RRT. Therefore, this outcome is subjective and imprecise, and to what extent it might have biased the outcome is unclear. Successful discontinuations of RRT, spontaneous improvement in azotaemia, or improvement in urinary creatinine clearance are parameters that could assess recovery in an objective way.4

I declare no competing interests.

Tukaram Ekanath Jamale

tukaramjamale@yahoo.co.in

Seth GS Medical College and King Edward Memorial Hospital, Mumbai 400012, India

1 Gaudry S, Hajage D, Martin-Lefevre L, et al. Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, openlabel, randomised, controlled trial. Lancet 2021; 397: 1293?300.

2 Steiner RW, Coggins C, Carvalho AC. Bleeding time in uremia: a useful test to assess clinical bleeding. Am J Hematol 1979; 7: 107?17.

3 Bleck TP, Smith MC, Pierre-Louis SJ, Jares JJ, Murray J, Hansen CA. Neurologic complications of critical medical illnesses. Crit Care Med 1993; 21: 98.

4 Kelly YP, Waikar SS, Mendu ML. When to stop renal replacement therapy in anticipation of renal recovery in AKI: the need for consensus guidelines. Semin Dial 2019; 32: 205?09.

Authors' reply

We thank Tukaram E Jamale for their interest in our work in the AKIKI 2 trial.1 We agree there is no parallelism between the degree of uraemia and the occurrence of life-threatening metabolic complications during acute kidney injury (AKI). Complications, such as severe pulmonary oedema unresponsive to diuretics, severe hyperkalaemia, or severe metabolic acidosis, are considered to be mandatory indications for renal replacement therapy (RRT) by all experts.2 Jamale has added uraemic bleeding and encephalopathy to the list of mandatory indications for RRT. However, these two particular conditions are more often observed in patients with advanced chronic kidney disease than in those with AKI and are difficult to diagnose with certainty in critically ill patients who might have many other causes (eg, sepsis and sedation) for these complications. In fact, these two precise complications are not mentioned among formal indications for RRT in most guidelines on AKI management due to their rarity. We agree that if such complications can be attributed with certainty to AKI itself, they would constitute an obvious indication for RRT. As such, randomising patients with these kinds of dangerous complications to immediate or delayed RRT would be unethical. All randomised controlled trials investigating RRT in patients with AKI (ie, AKIKI,3 IDEAL-ICU,4 STARRT-AKI5), as well as one by Jamale and colleagues,6 randomly assigned patients without any such severe complication. Notably, in the study by Jamale and colleagues,6 in which no patient was mechanically ventilated at baseline, the term uraemic bleeding does not appear. Therefore, it can be assumed

Vol 398 October 2, 2021

1215

Philippe Huguen/AFP/Getty Images

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download