IgG4-related disease and Rosai-Dorfman-Destombes disease

[Pages:2]Correspondence

Franklin Jacome/Agencia Press South/Getty Images

3 GloPID-R, UKCDR, and COVID-19 Clinical Research Coalition Cross-Working Group on COVID-19 Research in LMICs. Priorities for COVID-19 research response and preparedness in low-resource settings. Lancet 2021; 397: 1866?68.

4 US Food and Drug Administration. COVID-19 vaccines. 2021. . gov/emergency-preparedness-andresponse/coronavirus-disease-2019covid-19/covid-19-vaccines (accessed May 28, 2021).

5 European Medicines Agency. COVID-19 vaccines: authorised. 2021. . europa.eu/en/human-regulatory/overview/ public-health-threats/coronavirus-diseasecovid-19/treatments-vaccines/vaccinescovid-19/covid-19-vaccines-authorised #authorised-covid-19-vaccines-section (accessed Aug 14, 2021).

6 WHO. Emergency use designation of COVID-19 candidate vaccines: ethical considerations for current and future COVID-19 placebo-controlled vaccine trials and trial unblinding. Policy brief. Dec 18, 2020. publications/i/item/WHO-2019-nCoV-Policy_ Brief-EUD_placebo-controlled_vaccine_ trials-2020.1 (accessed May 25, 2021).

Authors' reply

We thank Ivan Sisa and colleagues for their comments on our Correspondence,1 but we still worry about the marginalisation of scientific production from lowincome and middle-income countries (LMICs). Indeed, these nations usually have scarce public resources to invest in science and, consequently, tend to produce fewer indexed publica tions compared with high-income countries (HICs). However, such metrics restrict the understanding of academic production to the accrual of articles in English-speaking scientific journals based in HICs and, therefore, to an imperfect appraisal of the impact of their discoveries and the value of the science only in relation to their own realities. Similarly, it is quite short-sighted to assess the scientific power of HICs as the amount of knowledge and products that LMICs adopt and buy from them, rather than as the degree of scientific sovereignty that the latter can develop. Furthermore, reducing the concept of innovation to the unilateral transfer of knowledge from HICs to the rest of the world, where vaccines and medicines are tested

rather than developed, actually contradicts the very purpose of scientific pursuits.

For LMICs to pursue scientific advancement to the same extent as HICs, they would need to dismiss the pluralities of knowledge that make their settings diverse and enriching outside of the laboratory and the clinic. In consequence, LMICs would have to privilege a medicalised version of health and life over other definitions and understandings of health and wellbeing. Even if this path were not pursued, it should not be demanded that LMICs relinquish a key presence on the global stage. Patients, consumers, doctors, and researchers in LMICs should not be required to validate methods and results of trials devised in HICs, without strengthening local capacity in research, technological development, and production of medicines (including vaccines) to become an increasingly equal counterpart across research cycles. Ultimately, appraising scientific innovation in terms of consumable knowledge without regard to local capacities and diverse wellbeing undervalues the importance of scientific sovereignty.

Any collaboration between governments, or academic or public and private institutions, across countries with different levels of income should aim towards scien tific sovereignty and, eventually, the dissemination of knowledge in the reverse direction. Inter national instruments, agreements, and funders should ensure there are policies in place to promote equity and to ultimately guarantee egalitarian scientific collaborations. Meanwhile, effective vaccines and medicines that are crucial in dealing with public health problems, when available, should be considered global public goods to be distrib uted across countries swiftly, in accordance with global solidarity mechanisms.

We declare no competing interests.

*Irene Torres, Barbara Profeta, Cristiani Vieira Machado, Osvaldo Artaza, Daniel Lopez-Cevallos, JaHyun Kang

irene.torres@octaedro.edu.ec

Fundaci?n Octaedro, Quito 170505, Ecuador (IT); Fribourg, Switzerland (BP); Oswaldo Cruz Foundation-Fiocruz, Rio de Janeiro, Brazil (CVM); School of Language, Culture and Society, Oregon State University, Corvallis, OR, USA (DL-C); Facultad de Ciencias de la Salud, Universidad de las Am?ricas, Santiago de Chile, Chile (OA); College of Nursing and Research Institute of Nursing Science, Seoul National University, Seoul, South Korea (JK)

1 Torres I, Lopez-Cevallos D, Artaza O, et al. Vaccine scarcity in LMICs is a failure of global solidarity and multilateral instruments. Lancet 2021; 397: 1804.

IgG4-related disease and Rosai-DorfmanDestombes disease

We appreciated reading the expert Seminar on histiocytosis by Jean-Fran?ois Emile and colleagues.1 However, we wish to clarify the importance of increased IgG4positive plasma cells seen in some patients with Rosai-DorfmanDestombes disease (RDD). First, hyper-IgG4 syndrome is a misnomer; the correct term is IgG4-related disease (IgG4-RD), and RDD should not be considered a subtype of IgG4-RD or vice versa.2 Although there are overlapping clinical features between the two conditions (eg, lymphadenopathy, pancreatitis, and hypertrophic pachymeningitis), each disease has distinct clinical features, pathophysiology, and treatment requirements. For example, cutaneous and subcutaneous disease is the most common extranodal presentation of RDD, whereas IgG4-RD rarely involves the skin.

IgG4-RD is so named because of the prominence of IgG4-positive plasma cells in affected tissues and increased IgG4 concentrations in serum. A subset of patients with RDD also

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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

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