Next Article in Journal
Plasma Biomarkers for Hypertension-Mediated Organ Damage Detection: A Narrative Review
Next Article in Special Issue
Unraveling TAFRO Syndrome: An In-Depth Look at the Pathophysiology, Management, and Future Perspectives
Previous Article in Journal
Prevalence of Dysmagnesemia among Patients with Diabetes Mellitus and the Associated Health Outcomes: A Cross-Sectional Study
Previous Article in Special Issue
Investigation of the Effect of Therapeutic Plasma Exchange for TAFRO Syndrome: A Pilot Study
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 12
Issue 5
10.3390/biomedicines12051070
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Case Report

Tacrolimus Treatment for TAFRO Syndrome

by
Taiichiro Shirai
1,2,3,*,
Shinya Ichikawa
1 and
Jun Saegusa
1
1
Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
2
Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
3
Department of Immune Response Dynamics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
*
Author to whom correspondence should be addressed.
Biomedicines 2024, 12(5), 1070; https://doi.org/10.3390/biomedicines12051070
Submission received: 11 April 2024 / Revised: 8 May 2024 / Accepted: 10 May 2024 / Published: 12 May 2024
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
Browse Figures
Versions Notes

Abstract

TAFRO syndrome is an acute systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. While its lymph node pathology is similar to that of idiopathic multicentric Castleman disease (iMCD), the clinical features of TAFRO syndrome differ from those of typical iMCD, as they include a more aggressive clinical course and high mortality. However, an optimal treatment strategy for TAFRO syndrome has not yet been established, owing to a poor understanding of its pathogenesis. The limited cases we encountered suggest that tacrolimus treatment in combination with glucocorticoids may potentially be effective and well tolerated as an initial treatment, and hold promise as a glucocorticoid-sparing agent. Herein, we report an additional case and review the sparse literature available regarding TAFRO syndrome treated via tacrolimus.

1. Introduction

Castleman disease (CD) is a rare lymphoproliferative disorder that involves single (unicentric) or multiple (multicentric) lymph nodes [1]. Multicentric CD (MCD) is further subdivided into human herpesvirus type-8 (HHV-8)-associated MCD; polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome-associated MCD; and idiopathic MCD (iMCD) [2]. In 2010, Takai et al. first reported three Japanese cases with fever, thrombocytopenia, pleural effusion and ascites, hepatosplenomegaly, and reticulin fibrosis of the bone marrow, proposing a new disease entity [3]. The systemic inflammatory disorder with a constellation of symptoms such as thrombocytopenia, anasarca (edema, pleural effusion, and ascites), fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (hepatosplenomegaly and lymphadenopathy) was named TAFRO syndrome, derived from the acronym of its symptoms [4]. An epidemiologic analysis of TAFRO syndrome in Japan estimated an annual incidence rate of 0.9–4.9 per million [5]. The etiology of TAFRO syndrome is undetermined; however, patients with this syndrome often have generalized lymphadenopathy, and their lymph node pathologies are typically similar to that of iMCD, classified into hypervascular, plasma cell (or plasmacytic), and mixed types [2,6]. Therefore, TAFRO syndrome is sometimes considered a subtype of iMCD (iMCD-TAFRO), whereas iMCD without TAFRO syndrome is described as “not otherwise specified” (iMCD-NOS) [2]. However, the nature of iMCD-TAFRO is different from that of iMCD-NOS, with a more aggressive clinical course and high mortality rate that is associated with refractory ascites and thrombocytopenia [7,8]. These unique clinical and laboratory features suggest that iMCD-TAFRO is distinct from iMCD.
Accumulating evidence on the pathogenesis of iMCD suggests that aberrant interleukin-6 (IL-6) signaling is a key driver of iMCD-NOS [9]. IL-6 is a multifunctional pro-inflammatory cytokine that induces B-cell and plasma cell maturation, leading to increased immunoglobulin production, and stimulates megakaryocyte maturation, typically resulting in thrombocytosis [10]. The intensity of iMCD-NOS symptoms correlates with serum IL-6 levels, which can be highly elevated during flare-ups [11]. However, in iMCD-TAFRO, IL-6 is only mildly elevated, and the typical clinical features of iMCD-NOS associated with excess IL-6, such as polyclonal hypergammaglobulinemia and thrombocytosis, are absent [8]. This suggests that IL-6 may not be the primary pathological driver of iMCD-TAFRO and that its exact pathophysiology remains to be elucidated. Currently, the international consensus treatment guidelines recommend anti-IL-6 therapy (tocilizumab or siltuximab) as the first-line treatment for iMCD-TAFRO [12]. However, evidence of an association between serum IL-6 levels and the efficacy of anti-IL-6 therapies for treating iMCD-TAFRO remains limited [8]. Treatment failure with anti-IL-6 therapy has been reported in 50% of iMCD-TAFRO cases [12]. Therefore, optimal treatment strategies for TAFRO syndrome are urgently needed.
Cyclosporine A, a calcineurin inhibitor, has been used to treat TAFRO syndrome, particularly for improving persistent ascites and thrombocytopenia [13,14,15,16,17]. Notably, this treatment may be useful in cases of TAFRO syndrome that are refractory to anti-IL-6 therapy [14,15]. Cyclosporine A exerts an immunosuppressive effect by inhibiting the dephosphorylation of the nuclear factors of activated T-cells, by binding to calcineurin [18,19]. Tacrolimus is another calcineurin inhibitor, and we previously reported the first cases of TAFRO syndrome successfully treated with tacrolimus, including one case that was refractory to anti-IL-6 therapy and intolerant to cyclosporine A [20]. Herein, we report an additional case of TAFRO syndrome effectively treated with tacrolimus and glucocorticoids, in which tacrolimus was also useful as a glucocorticoid-sparing agent. Moreover, we review the literature on TAFRO syndrome treated with tacrolimus and explore the efficacy of this approach.

2. Case Presentation

A 33-year-old Japanese woman with no prior medical history was referred to a hospital with a 3-week history of abdominal distension and a fever of 38.2 °C. Upon physical examination, the patient exhibited swollen cervical and axillary lymph nodes (diameter: 1 cm), mild abdominal tenderness, and pitting edema of the lower legs. Laboratory studies revealed thrombocytopenia (platelet count, 65,000/μL [reference range, 158,000–358,000/μL]); anemia (hemoglobin concentration, 7.8 g/dL [reference range, 11.6–14.8 g/dL]); the absence of hypergammaglobulinemia (serum immunoglobulin G concentration, 1137 mg/dL [reference range, 861–1747 mg/dL]); elevated serum levels of alkaline phosphatase (919 U/L [reference range, 106–322 U/L]), C-reactive protein (CRP, 17.22 mg/dL [reference range, 0.00–0.14 mg/dL]), soluble IL-2 receptor (sIL-2R, 1702 U/mL [reference range, 122–496 U/mL]), and IL-6 (55.0 pg/mL [reference range, 0.0–7.0 pg/mL]); elevated plasma levels of vascular endothelial growth factor (VEGF, 297.0 pg/mL [reference range, 0.0–38.3 pg/mL]); and mild renal dysfunction (estimated glomerular filtration rate, eGFR; 58 mL/min/1.73 m2) with microhematuria. The test results for autoantibodies such as anti-double-stranded DNA and anti-neutrophil cytoplasmic antibodies, as well as viruses such as HHV-8, human immunodeficiency virus, and Epstein–Barr virus, were negative. Computed tomography (CT) revealed mild cervical and axillary lymphadenopathy (1–1.5 cm in diameter), bilateral pleural effusions, ascites, and hepatosplenomegaly. Cervical lymph node biopsy revealed the expansion of the interfollicular zone with vascular proliferation and plasmacytic infiltrates (Figure 1). A bone marrow biopsy revealed hyperplasia of the megakaryocytes and reticulin fibrosis. We found no evidence of infectious, malignant, or autoimmune diseases that can mimic TAFRO syndrome [8,21,22]. Additionally, the diagnosis of hemophagocytic lymphohistiocytosis (HLH) was not established according to the HLH-2004 criteria [23] or the HScore for reactive hemophagocytic syndrome [24]. Thus, the patient met the diagnostic criteria for TAFRO syndrome proposed by both the Japanese TAFRO Syndrome Research Team [21,25] and the Castleman Disease Collaborative Network [8]. The disease severity was estimated to be slightly severe (grade 3 out of 5) according to the 2019 updated disease severity classification for TAFRO syndrome [21].
Half of the cases of TAFRO syndrome are reported to be unresponsive to anti-IL-6 therapy [12], and we have previously reported cases of TAFRO syndrome successfully treated with tacrolimus that presented thrombocytopenia and ascites with less severe disease activity, one of which proved refractory to anti-IL-6 therapy and resulted in septic shock [20]. In light of these facts, after obtaining informed consent from the patient, we initiated methylprednisolone (mPSL) pulse therapy at 1000 mg/day for three consecutive days, followed by 60 mg/day (1 mg/kg/day) of oral PSL and 4 mg/day (0.07 mg/kg/day) of tacrolimus, targeting a trough concentration of 5–10 ng/mL (Figure 2). This alleviated the patient’s fever, thrombocytopenia, and renal dysfunction. The abdominal distension also gradually subsided, and CT showed the complete resolution of the bilateral pleural effusions and ascites after 4 weeks of treatment. Tacrolimus was continued, and glucocorticoids were tapered and eventually discontinued. The patient has had an uneventful course without relapse for >4 years.

3. Discussion

Although a standard treatment strategy for TAFRO syndrome has not yet been established, we report an additional case of TAFRO syndrome successfully treated with tacrolimus. Our findings suggest that tacrolimus in combination with glucocorticoids may be an effective and well-tolerated initial treatment for TAFRO syndrome, while showing promise as a glucocorticoid-sparing agent. According to a recent surveillance study in Japan, most patients with TAFRO syndrome receive glucocorticoids as a first-line treatment [13]. Tocilizumab, cyclosporine A, and rituximab (an anti-CD20 antibody for B-cell depletion) are commonly used to treat glucocorticoid-resistant patients [13]. However, despite these immunosuppressive treatments, the mortality rate remains high for patients with this syndrome [7]. Furthermore, in some cases, severe infections occur during the treatment, which can be fatal according to our review of the literature (Table 1). These facts highlight a need for the development of specific therapeutic strategies.
A challenge in finding optimal treatments for TAFRO syndrome is the incomplete understanding of its pathogenesis. Previous studies have shown distinct proteomic profiles for iMCD-TAFRO and iMCD-NOS, suggesting that diverse driving factors underlie the iMCD disease spectrum [51]. In this context, emerging evidence points to activated T-cells as potential pathogenic drivers of iMCD-TAFRO. Iwaki et al. reported that C-X-C motif chemokine ligand 10 (CXCL10), also known as interferon γ-induced protein 10, exhibited higher levels in patients with iMCD-TAFRO compared to those with iMCD-NOS during flare-ups [52]. CXCL10 plays an important role in recruiting activated T-cells to inflammation sites [53]. Fajgenbaum et al. found that sIL-2Rα, a marker of T-cell activation, and VEGF-A were upregulated during flare-ups in patients with iMCD-TAFRO who were refractory to anti-IL-6 therapy. Additionally, these patients exhibited increased numbers of activated CD8+ T-cells [54]. Serum proteomic analysis revealed the enrichment of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) pathway in these cases, and sirolimus—an mTOR inhibitor—proved to be effective [54]. Furthermore, the symptoms of capillary leak syndrome, an adverse effect of IL-2 immunotherapy, reveal some overlap with those of TAFRO syndrome, suggesting the possible contribution of IL-2 to its pathogenesis [14].
Given the proposed pathogenesis, treating TAFRO syndrome with calcineurin inhibitors such as cyclosporine A and tacrolimus, which target activated T-cells and inhibit the secretion of proinflammatory cytokines (particularly IL-2), emerges as a rational therapeutic strategy. Although cyclosporine A has been widely used in the treatment of TAFRO syndrome [13], information regarding cases treated using tacrolimus remains limited. To the best of our knowledge, only four studies have reported the use of tacrolimus treatment for TAFRO syndrome [20,38,55,56] (Table 2), excluding one in which the duration of tacrolimus use was markedly short to evaluate its efficacy [33]. Among these studies, we first described two cases of TAFRO syndrome that were successfully treated using tacrolimus [20].
The first case [20] is a 68-year-old Japanese woman with a 4-week history of abdominal distension and a fever of 38.1 °C. Laboratory studies revealed anemia, thrombocytopenia (platelet count, 38,000/μL), elevated serum levels of CRP (2.70 mg/dL), and renal dysfunction (eGFR, 25.5 mL/min/1.73 m2). CT showed generalized lymphadenopathy (1–1.5 cm in diameter), bilateral pleural effusion, massive ascites, and hepatosplenomegaly. The histopathological findings for the lymph nodes were compatible with the mixed type of CD. Moreover, reticulin fibrosis and megakaryocytic hyperplasia were found in the bone marrow. These findings met the diagnostic criteria for TAFRO syndrome, and the disease severity was estimated to be slightly severe (grade 3 out of 5). Oral PSL at 60 mg/day (1 mg/kg/day) improved the renal dysfunction but did not resolve the thrombocytopenia and massive ascites. Additional treatment with tocilizumab failed to improve the symptoms, but rather the patient developed septic shock due to empyema, necessitating the discontinuation of tocilizumab. Moreover, cyclosporine A was discontinued within a week due to its hepatotoxicity. Therefore, we initiated tacrolimus at 4 mg/day (0.07 mg/kg/day), targeting a trough concentration of 5–10 ng/mL, which dramatically alleviated thrombocytopenia and ascites. With the use of tacrolimus, glucocorticoids were successfully tapered. The patient has had an uneventful course without relapse for >6 years.
The second case [20] is a 17-year-old Japanese man with a 4-week history of abdominal pain and a fever of 38.8 °C. His progressive symptoms included anemia, thrombocytopenia (platelet count, 68,000/μL), elevated serum levels of CRP (23.00 mg/dL), and renal dysfunction (eGFR, 50.6 mL/min/1.73 m2) with microhematuria. CT revealed mild cervical and axillary lymphadenopathy (1–1.5 cm in diameter), bilateral pleural effusion, ascites, and hepatosplenomegaly. The histopathological findings of the lymph nodes were compatible with the mixed type of CD, and the reticulin fibrosis and normoplasia of megakaryocytes were found in the bone marrow. A diagnosis of TAFRO syndrome was made and the disease severity was estimated to be slightly severe (grade 3 out of 5). During the course of the disease, the patient presented with the sudden onset of cardiogenic shock without evidence of takotsubo cardiomyopathy, myocardial infarction, or viral myocarditis. Echocardiography showed the severe and diffuse hypokinesis of both ventricles and moderate pericardial effusion. In addition to mPSL pulse therapy at 1000 mg/day for three consecutive days and 60 mg/day (1 mg/kg/day) of oral PSL, we started 4 mg/day (0.07 mg/kg/day) of tacrolimus, targeting a trough concentration of 5–10 ng/mL. This improved the symptoms of TAFRO syndrome, including thrombocytopenia and anasarca, and repeat echocardiography revealed normal wall motion without pericardial effusion 4 weeks after initiation of the treatment (Figure 3). Tacrolimus was well tolerated and continued while the glucocorticoids were tapered and eventually discontinued. The patient has had an uneventful course without relapse for >5 years.
In all three cases we encountered, including the present one, tacrolimus in combination with glucocorticoids was effective as induction therapy for the symptoms of TAFRO syndrome, including, but not limited to, thrombocytopenia and ascites. Additionally, tacrolimus was useful as a glucocorticoid-sparing agent. Considering the uneventful course without relapse for several years observed in these patients, tacrolimus treatment alone or with low-dose glucocorticoids could potentially serve as maintenance therapy for TAFRO syndrome. The disease severity of TAFRO syndrome in these patients was estimated to be slightly severe (grade 3 out of 5) according to the 2019 updated disease severity classification [21]. While the precise type of patients or specific disease symptoms that were most effectively targeted by tacrolimus remain unclear, treatment with tacrolimus might be particularly effective in cases with thrombocytopenia and ascites, especially when the disease activity is not severe.
As described above, we reported cardiomyopathy, a rare complication of TAFRO syndrome, which was reversed upon treatment with tacrolimus and glucocorticoids. To date, cardiomyopathy in TAFRO syndrome has been reported in only a few cases [57,58,59], one of which was refractory to anti-IL-6 therapy, suggesting that other proinflammatory cytokines may be involved [57]. Given the documented association between high-dose IL-2 immunotherapy and reversible cardiomyopathy [60], and our case’s successful treatment outcome with tacrolimus, IL-2 might contribute to cardiomyopathy in TAFRO syndrome, although the mechanism remains poorly understood.
In addition to adult cases, a preprint study by Goteti et al. described a case of TAFRO syndrome in an infant treated with tacrolimus [55]. The patient was initially treated with tocilizumab and glucocorticoids. However, the anasarca persisted; therefore, tacrolimus was administered, which proved to be effective. The tacrolimus was continued without adverse events and the glucocorticoids were successfully tapered [55]. This case suggests that tacrolimus may also be effective and well tolerated in infants with TAFRO syndrome.
Conversely, two other reports have described cases of TAFRO syndrome where tacrolimus was ineffective. Nagai et al. reported a possible recurrent case of TAFRO syndrome that developed in a kidney transplant recipient who was taking daily immunosuppressants, including tacrolimus [56]. The patient was treated with tacrolimus and mycophenolate mofetil, in addition to glucocorticoids; however, this proved ineffective, and the patient eventually died [56]. Considering the possibility of multiple pathogeneses of TAFRO syndrome, including T-cell and B-cell/plasma cell-dominant variants, it may be reasonable to consider rituximab or tocilizumab as first-line treatments instead of tacrolimus, particularly in patients who are already taking tacrolimus at the onset of TAFRO syndrome. Moreover, Abe et al. reported cases of TAFRO syndrome that were refractory to tacrolimus treatment but were effectively treated with cyclosporine A [38]. Both cyclosporine A and tacrolimus exert their immunosuppressive effects by binding to calcineurin on activated T-cells; however, they bind to different binding proteins, cyclophilins, and FK506-binding proteins, respectively [18,19]. This may explain the differences in their efficacy levels and adverse events in individual cases of TAFRO syndrome. In this regard, cyclosporine A exhibits hepatotoxicity during the treatment of some cases (Table 1), and thus replacing cyclosporine A with tacrolimus may be beneficial.

4. Conclusions

Given that TAFRO syndrome is a relatively newly recognized disease of unknown etiology, information on the best therapeutic strategies is limited. Currently, some molecular targeted therapies, including tocilizumab, siltuximab, and rituximab, have been used; however, their efficacy is not satisfactory. Herein, we report an additional case and review the existing literature on tacrolimus treatment for TAFRO syndrome. Although based on a small number of cases, treatment with tacrolimus in combination with glucocorticoids may be potentially effective and well tolerated in TAFRO syndrome, especially in cases presenting with thrombocytopenia and ascites with less severe disease activity. In addition, tacrolimus treatment may be useful as a glucocorticoid-sparing agent and as a maintenance therapy in TAFRO syndrome. One of the major hurdles in developing optimal treatment strategies for TAFRO syndrome is the difficulty associated with understanding its pathogenesis. Again, the efficacy of tacrolimus treatment discussed here is based on a limited number of cases, with reports on tacrolimus-refractory cases. Considering the possibility that multiple factors drive TAFRO syndrome, further research is needed to determine the specific patients and symptom profiles that will respond to tacrolimus. Ultimately, gaining a comprehensive understanding of the pathogenesis of TAFRO syndrome would provide insight into the rationale of tacrolimus treatment and contribute to the development of optimal therapeutic strategies.

Author Contributions

Writing—original draft preparation, T.S.; writing—review and editing, T.S. and S.I.; supervision, J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported in part by the Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JP24K18465 to T.S.). T.S. was supported by the KIBOU project fellowship from the Japanese Society for Immunology.

Institutional Review Board Statement

Ethical review and approval were waived for this study because they are not required for case reports.

Informed Consent Statement

Informed consent was obtained from all patients involved in the study.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors upon request.

Acknowledgments

We thank the members of the Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, for their helpful comments on the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Carbone, A.; Borok, M.; Damania, B.; Gloghini, A.; Polizzotto, M.N.; Jayanthan, R.K.; Fajgenbaum, D.C.; Bower, M. Castleman disease. Nat. Rev. Dis. Primers 2021, 7, 84. [Google Scholar] [CrossRef]
  2. Dispenzieri, A.; Fajgenbaum, D.C. Overview of Castleman disease. Blood 2020, 135, 1353–1364. [Google Scholar] [CrossRef] [PubMed]
  3. Takai, K.; Nikkuni, K.; Shibuya, H.; Hashidate, H. Thrombocytopenia with mild bone marrow fibrosis accompanied by fever, pleural effusion, ascites and hepatosplenomegaly. Rinsho Ketsueki 2010, 51, 320–325. [Google Scholar] [PubMed]
  4. Kawabata, H.; Takai, K.; Kojima, M.; Nakamura, N.; Aoki, S.; Nakamura, S.; Kinoshita, T.; Masaki, Y. Castleman-Kojima disease (TAFRO syndrome): A novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly: A status report and summary of Fukushima (6 June 2012) and Nagoya meetings (22 September 2012). J. Clin. Exp. Hematop. 2013, 53, 57–61. [Google Scholar] [PubMed]
  5. Masaki, Y.; Kawabata, H.; Fujimoto, S.; Kawano, M.; Iwaki, N.; Kotani, T.; Nakashima, A.; Kurose, N.; Takai, K.; Suzuki, R.; et al. Epidemiological analysis of multicentric and unicentric Castleman disease and TAFRO syndrome in Japan. J. Clin. Exp. Hematop. 2019, 59, 175–178. [Google Scholar] [CrossRef] [PubMed]
  6. Kurose, N.; Futatsuya, C.; Mizutani, K.-i.; Kumagai, M.; Shioya, A.; Guo, X.; Aikawa, A.; Nakada, S.; Fujimoto, S.; Kawabata, H.; et al. The clinicopathological comparison among nodal cases of idiopathic multicentric Castleman disease with and without TAFRO syndrome. Hum. Pathol. 2018, 77, 130–138. [Google Scholar] [CrossRef] [PubMed]
  7. Fujimoto, S.; Sakai, T.; Kawabata, H.; Kurose, N.; Yamada, S.; Takai, K.; Aoki, S.; Kuroda, J.; Ide, M.; Setoguchi, K.; et al. Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease? Am. J. Hematol. 2019, 94, 975–983. [Google Scholar] [CrossRef] [PubMed]
  8. Iwaki, N.; Fajgenbaum, D.C.; Nabel, C.S.; Gion, Y.; Kondo, E.; Kawano, M.; Masunari, T.; Yoshida, I.; Moro, H.; Nikkuni, K.; et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am. J. Hematol. 2016, 91, 220–226. [Google Scholar] [CrossRef]
  9. Fajgenbaum, D.C.; van Rhee, F.; Nabel, C.S. HHV-8-negative, idiopathic multicentric Castleman disease: Novel insights into biology, pathogenesis, and therapy. Blood 2014, 123, 2924–2933. [Google Scholar] [CrossRef]
  10. Tanaka, T.; Narazaki, M.; Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. 2014, 6, a016295. [Google Scholar] [CrossRef]
  11. Casper, C.; Chaturvedi, S.; Munshi, N.; Wong, R.; Qi, M.; Schaffer, M.; Bandekar, R.; Hall, B.; van de Velde, H.; Vermeulen, J.; et al. Analysis of inflammatory and anemia-related biomarkers in a randomized, double-blind, placebo-controlled study of siltuximab (anti-il6 monoclonal antibody) in patients with multicentric Castleman disease. Clin. Cancer Res. 2015, 21, 4294–4304. [Google Scholar] [CrossRef] [PubMed]
  12. van Rhee, F.; Voorhees, P.; Dispenzieri, A.; Fosså, A.; Srkalovic, G.; Ide, M.; Munshi, N.; Schey, S.; Streetly, M.; Pierson, S.K.; et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood 2018, 132, 2115–2124. [Google Scholar] [CrossRef] [PubMed]
  13. Fujimoto, S.; Kawabata, H.; Sakai, T.; Yanagisawa, H.; Nishikori, M.; Nara, K.; Ohara, S.; Tsukamoto, N.; Kurose, N.; Yamada, S.; et al. Optimal treatments for TAFRO syndrome: A retrospective surveillance study in Japan. Int. J. Hematol. 2021, 113, 73–80. [Google Scholar] [CrossRef] [PubMed]
  14. Konishi, Y.; Takahashi, S.; Nishi, K.; Sakamaki, T.; Mitani, S.; Kaneko, H.; Mizutani, C.; Ukyo, N.; Hirata, H.; Tsudo, M. Successful treatment of TAFRO syndrome, a variant of multicentric Castleman’s disease, with cyclosporine A: Possible pathogenetic contribution of interleukin-2. Tohoku J. Exp. Med. 2015, 236, 289–295. [Google Scholar] [CrossRef] [PubMed]
  15. Yamaga, Y.; Tokuyama, K.; Kato, T.; Yamada, R.; Murayama, M.; Ikeda, T.; Yamakita, N.; Kunieda, T. Successful treatment with cyclosporin A in tocilizumab-resistant TAFRO syndrome. Intern. Med. 2016, 55, 185–190. [Google Scholar] [CrossRef] [PubMed]
  16. Inoue, M.; Ankou, M.; Hua, J.; Iwaki, Y.; Hagihara, M.; Ota, Y. Complete resolution of TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) after immunosuppressive therapies using corticosteroids and cyclosporin A: A case report. J. Clin. Exp. Hematop. 2013, 53, 95–99. [Google Scholar] [CrossRef]
  17. Takasawa, N.; Sekiguchi, Y.; Takahashi, T.; Muryoi, A.; Satoh, J.; Sasaki, T. A case of TAFRO syndrome, a variant of multicentric Castleman’s disease, successfully treated with corticosteroid and cyclosporine A. Mod. Rheumatol. 2019, 29, 198–202. [Google Scholar] [CrossRef] [PubMed]
  18. Mukherjee, S.; Mukherjee, U. A comprehensive review of immunosuppression used for liver transplantation. J. Transplant. 2009, 2009, 701464. [Google Scholar] [CrossRef] [PubMed]
  19. Kitahara, K.; Kawai, S. Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis. Curr. Opin. Rheumatol. 2007, 19, 238–245. [Google Scholar] [CrossRef]
  20. Shirai, T.; Onishi, A.; Waki, D.; Saegusa, J.; Morinobu, A. Successful treatment with tacrolimus in TAFRO syndrome: Two case reports and literature review. Medicine 2018, 97, e11045. [Google Scholar] [CrossRef]
  21. Masaki, Y.; Kawabata, H.; Takai, K.; Tsukamoto, N.; Fujimoto, S.; Ishigaki, Y.; Kurose, N.; Miura, K.; Nakamura, S.; Aoki, S.; et al. 2019 Updated diagnostic criteria and disease severity classification for TAFRO syndrome. Int. J. Hematol. 2020, 111, 155–158. [Google Scholar] [CrossRef] [PubMed]
  22. Nishimura, Y.; Fajgenbaum, D.C.; Pierson, S.K.; Iwaki, N.; Nishikori, A.; Kawano, M.; Nakamura, N.; Izutsu, K.; Takeuchi, K.; Nishimura, M.F.; et al. Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease. Am. J. Hematol. 2021, 96, 1241–1252. [Google Scholar] [CrossRef]
  23. Henter, J.-I.; Horne, A.; Aricó, M.; Egeler, R.M.; Filipovich, A.H.; Imashuku, S.; Ladisch, S.; McClain, K.; Webb, D.; Winiarski, J.; et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 2007, 48, 124–131. [Google Scholar] [CrossRef] [PubMed]
  24. Fardet, L.; Galicier, L.; Lambotte, O.; Marzac, C.; Aumont, C.; Chahwan, D.; Coppo, P.; Hejblum, G. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014, 66, 2613–2620. [Google Scholar] [CrossRef] [PubMed]
  25. Masaki, Y.; Kawabata, H.; Takai, K.; Kojima, M.; Tsukamoto, N.; Ishigaki, Y.; Kurose, N.; Ide, M.; Murakami, J.; Nara, K.; et al. Proposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, 2015 version. Int. J. Hematol. 2016, 103, 686–692. [Google Scholar] [CrossRef] [PubMed]
  26. Yanagiya, R.; Suzuki, T.; Nakamura, S.; Fujita, K.; Oyama, M.; Okuyama, A.; Sugasawa, K.; Nakayama, T.; Suzuki, Y.; Ishizawa, K.; et al. TAFRO syndrome presenting with retroperitoneal panniculitis-like computed tomography findings at disease onset. Intern. Med. 2020, 59, 997–1000. [Google Scholar] [CrossRef]
  27. Oka, S.; Ono, K.; Nohgawa, M. Subclinical hypothyroidism in TAFRO syndrome. Intern. Med. 2019, 58, 2615–2620. [Google Scholar] [CrossRef] [PubMed]
  28. Nakamura, G.; Homma, N.; Kasai, A.; Kasami, T.; Makino, K.; Aoki, Y.; Wakaki, K.; Nakagawa, N. Magnetic resonance imaging of bone marrow for TAFRO syndrome. Mod. Rheumatol. 2019, 29, 551–557. [Google Scholar] [CrossRef]
  29. Fujiki, T.; Hirasawa, S.; Watanabe, S.; Iwamoto, S.; Ando, R. Successful treatment by tocilizumab without steroid in a very severe case of TAFRO syndrome. CEN Case Rep. 2017, 6, 105–110. [Google Scholar] [CrossRef]
  30. Yamagami, K.; Hanioka, Y.; Yao, S.; Nakamura, R.; Nakamura, T.; Ishii, N.; Goto, H. A case of TAFRO syndrome maintained in remission for 5 years after discontinuation of tocilizumab. Mod. Rheumatol. Case Rep. 2022, 7, 205–210. [Google Scholar] [CrossRef]
  31. Zhou, Q.; Zhang, Y.; Zhou, G.; Zhu, J. Kidney biopsy findings in two patients with TAFRO syndrome: Case presentations and review of the literature. BMC Nephrol. 2020, 21, 499. [Google Scholar] [CrossRef] [PubMed]
  32. Hashimoto, K.; Sano, T.; Honma, Y.; Ida, M.; Tominaga, H.; Sawada, A.; Abe, T.; Takahashi, H.; Shimada, Y.; Masaki, T.; et al. An autopsy case of TAFRO syndrome with membranoproliferative glomerulonephritis-like lesions. CEN Case Rep. 2019, 8, 48–54. [Google Scholar] [CrossRef] [PubMed]
  33. Ducoux, G.; Guerber, A.; Durel, C.A.; Asli, B.; Fadlallah, J.; Hot, A. Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome with bilateral adrenal hemorrhage in two Caucasian patients. Am. J. Case. Rep. 2020, 21, e919536. [Google Scholar] [CrossRef] [PubMed]
  34. Ono, S.; Yoshimoto, K.; Nishimura, N.; Yoneima, R.; Kawashima, H.; Kobayashi, T.; Tai, Y.; Miyamoto, M.; Tsushima, E.; Yada, N.; et al. Complete resolution of a case of TAFRO syndrome accompanied by mediastinal panniculitis, adrenal lesion, and liver damage with hyperbilirubinemia. Intern. Med. 2021, 60, 1303–1309. [Google Scholar] [CrossRef] [PubMed]
  35. Nagayama, Y.; Yamano, M.; Yagame, M.; Nariyama, T.; Takahashi, M.; Kawamoto, M.; Matsui, K. TAFRO syndrome as a cause of glomerular microangiopathy: A case report and literature review. BMC Nephrol. 2019, 20, 375. [Google Scholar] [CrossRef] [PubMed]
  36. Allegra, A.; Rotondo, F.; Russo, S.; Calabrò, L.; Maisano, V.; Bacci, F.; Musolino, C. Castleman–Kojima disease (TAFRO syndrome) in a Caucasian patient: A rare case report and review of the literature. Blood Cells Mol. Dis. 2015, 55, 206–207. [Google Scholar] [CrossRef]
  37. Yamamoto, S.; Wells, K.; Morita, K.; Tanigaki, K.; Muro, K.; Matsumoto, M.; Nakai, H.; Arai, Y.; Akizuki, S.; Takahashi, K.; et al. Severe TAFRO syndrome mimicking hepatorenal syndrome successfully treated with a multidisciplinary approach: A case report and literature review. Intern. Med. 2023, 62, 2715–2724. [Google Scholar] [CrossRef]
  38. Abe, N.; Kono, M.; Kono, M.; Ohnishi, N.; Sato, T.; Tarumi, M.; Yoshimura, M.; Sato, T.; Karino, K.; Shimizu, Y.; et al. Glycogen synthase kinase 3β/CCR6-positive bone marrow cells correlate with disease activity in multicentric Castleman disease-TAFRO. Br. J. Haematol. 2022, 196, 1194–1204. [Google Scholar] [CrossRef]
  39. Ohta, R.; Sano, C. Thrombocytopenia, Anasarca, Myelofibrosis, Renal dysfunction, and Organomegaly (TAFRO) Syndrome Initially Diagnosed as Fibromyalgia: A Case Report. Cureus 2023, 15, e42514. [Google Scholar] [CrossRef]
  40. Hayashi, M.; Wada, J.; Fujita, M.; Asano, T.; Matsuoka, N.; Fujita, Y.; Temmoku, J.; Matsumoto, H.; Yashio-Furuya, M.; Sato, S.; et al. TAFRO syndrome complicated by porto-sinusoidal vascular liver disease with portal hypertension: A case report. Clin. J. Gastroenterol. 2021, 14, 1711–1717. [Google Scholar] [CrossRef]
  41. Minomo, S.; Fujiwara, Y.; Sakashita, S.; Takamura, A.; Nagata, K. A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: A case report. J. Med. Case Rep. 2021, 15, 3. [Google Scholar] [CrossRef] [PubMed]
  42. Matsuhisa, T.; Takahashi, N.; Nakaguro, M.; Sato, M.; Inoue, E.; Teshigawara, S.; Ozawa, Y.; Kondo, T.; Nakamura, S.; Sato, J.; et al. Fatal case of TAFRO syndrome associated with over-immunosuppression: A case report and review of the literature. Nagoya J. Med. Sci. 2019, 81, 519–528. [Google Scholar] [PubMed]
  43. Fujiwara, Y.; Ito, K.; Takamura, A.; Nagata, K. The first case of thrombocytopenia, anasarca, fever, renal impairment or reticulin fibrosis, and organomegaly (TAFRO) syndrome with unilateral adrenal necrosis: A case report. J. Med. Case Reports 2018, 12, 295. [Google Scholar] [CrossRef] [PubMed]
  44. Kageyama, C.; Igawa, T.; Gion, Y.; Iwaki, N.; Tabata, T.; Tanaka, T.; Kondo, E.; Sakai, H.; Tsuneyama, K.; Nomoto, K.; et al. Hepatic Campylobacter jejuni infection in patients with Castleman-Kojima disease (idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome). Pathol. Int. 2019, 69, 572–579. [Google Scholar] [CrossRef] [PubMed]
  45. Coutier, F.; Meaux Ruault, N.; Crepin, T.; Bouiller, K.; Gil, H.; Humbert, S.; Bedgedjian, I.; Magy-Bertrand, N. A comparison of TAFRO syndrome between Japanese and non-Japanese cases: A case report and literature review. Ann. Hematol. 2018, 97, 401–407. [Google Scholar] [CrossRef] [PubMed]
  46. Kawabata, H.; Kotani, S.-i.; Matsumura, Y.; Kondo, T.; Katsurada, T.; Haga, H.; Kadowaki, N.; Takaori-Kondo, A. Successful treatment of a patient with multicentric castleman’s disease who presented with thrombocytopenia, ascites, renal failure and myelofibrosis using tocilizumab, an anti-interleukin-6 receptor antibody. Intern. Med. 2013, 52, 1503–1507. [Google Scholar] [CrossRef] [PubMed]
  47. Hibi, A.; Mizuguchi, K.; Yoneyama, A.; Kasugai, T.; Kamiya, K.; Kamiya, K.; Ito, C.; Kominato, S.; Miura, T.; Koyama, K. Severe refractory TAFRO syndrome requiring continuous renal replacement therapy complicated with Trichosporon asahii infection in the lungs and myocardial infarction: An autopsy case report and literature review. Ren. Replace. Ther. 2018, 4, 16. [Google Scholar] [CrossRef] [PubMed]
  48. Yamaguchi, Y.; Maeda, Y.; Shibahara, T.; Nameki, S.; Nakabayashi, A.; Komuta, K.; Mizuno, Y.; Yagita, M.; Manabe, Y.; Morita, T.; et al. Recovery from prolonged thrombocytopenia in patients with TAFRO syndrome: Case series and literature review. Mod. Rheumatol. Case Rep. 2020, 4, 302–309. [Google Scholar] [CrossRef]
  49. Wakiya, R.; Kameda, T.; Takeuchi, Y.; Ozaki, H.; Nakashima, S.; Shimada, H.; Kadowaki, N.; Dobashi, H. Sequential change in serum VEGF levels in a case of tocilizumab-resistant TAFRO syndrome treated effectively with rituximab. Mod. Rheumatol. Case Rep. 2021, 5, 145–151. [Google Scholar] [CrossRef]
  50. Tsurumi, H.; Fujigaki, Y.; Yamamoto, T.; Iino, R.; Taniguchi, K.; Nagura, M.; Arai, S.; Tamura, Y.; Ota, T.; Shibata, S.; et al. Remission of refractory ascites and discontinuation of hemodialysis after additional rituximab to long-term glucocorticoid therapy in a patient with TAFRO syndrome. Intern. Med. 2018, 57, 1433–1438. [Google Scholar] [CrossRef]
  51. Pierson, S.K.; Stonestrom, A.J.; Shilling, D.; Ruth, J.; Nabel, C.S.; Singh, A.; Ren, Y.; Stone, K.; Li, H.; van Rhee, F.; et al. Plasma proteomics identifies a ‘chemokine storm’ in idiopathic multicentric Castleman disease. Am. J. Hematol. 2018, 93, 902–912. [Google Scholar] [CrossRef] [PubMed]
  52. Iwaki, N.; Gion, Y.; Kondo, E.; Kawano, M.; Masunari, T.; Moro, H.; Nikkuni, K.; Takai, K.; Hagihara, M.; Hashimoto, Y.; et al. Elevated serum interferon γ-induced protein 10 kDa is associated with TAFRO syndrome. Sci. Rep. 2017, 7, 42316. [Google Scholar] [CrossRef] [PubMed]
  53. Dufour, J.H.; Dziejman, M.; Liu, M.T.; Leung, J.H.; Lane, T.E.; Luster, A.D. IFN-γ-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J. Immunol. 2002, 168, 3195–3204. [Google Scholar] [CrossRef] [PubMed]
  54. Fajgenbaum, D.C.; Langan, R.-A.; Japp, A.S.; Partridge, H.L.; Pierson, S.K.; Singh, A.; Arenas, D.J.; Ruth, J.R.; Nabel, C.S.; Stone, K.; et al. Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade–refractory idiopathic multicentric Castleman disease. J. Clin. Investig. 2019, 129, 4451–4463. [Google Scholar] [CrossRef] [PubMed]
  55. Goteti, S.; Johnson, A.; Williams, T.; Richardson, K.; Hogan, M. An infant with TAFRO syndrome: Case report and review of the literature. Authorea 2022. [Google Scholar] [CrossRef]
  56. Nagai, M.; Uchida, T.; Yamada, M.; Komatsu, S.; Ota, K.; Mukae, M.; Iwamoto, H.; Hirano, H.; Karube, M.; Kaname, S.; et al. TAFRO syndrome in a kidney transplant recipient that was diagnosed on autopsy: A case report. Front. Med. 2021, 8, 747678. [Google Scholar] [CrossRef] [PubMed]
  57. Hiramatsu, S.; Ohmura, K.; Tsuji, H.; Kawabata, H.; Kitano, T.; Sogabe, A.; Hashimoto, M.; Murakami, K.; Imura, Y.; Yukawa, N.; et al. Successful treatment by rituximab in a patient with TAFRO syndrome with cardiomyopathy. Nihon Rinsho Meneki Gakkai Kaishi 2016, 39, 64–71. [Google Scholar] [CrossRef] [PubMed]
  58. Yasuda, S.; Tanaka, K.; Ichikawa, A.; Watanabe, K.; Uchida, E.; Yamamoto, M.; Yamamoto, K.; Mizuchi, D.; Miura, O.; Fukuda, T. Aggressive TAFRO syndrome with reversible cardiomyopathy successfully treated with combination chemotherapy. Int. J. Hematol. 2016, 104, 512–518. [Google Scholar] [CrossRef] [PubMed]
  59. Moy, L.N.; Patel, M.; Eschbach, J.; Knouse, P.; Gálvez, Á. A case of TAFRO syndrome with DIC and neurologic and cardiac involvement. Clin. Case Rep. 2023, 11, e07340. [Google Scholar] [CrossRef]
  60. Goel, M.; Flaherty, L.; Lavine, S.; Redman, B.G. Reversible Cardiomyopathy After High-Dose Interleukin-2 Therapy. J. Immunother. 1992, 11, 225–229. [Google Scholar] [CrossRef]
Biomedicines 12 01070 g001
Figure 1. Histopathology of the cervical lymph node. The expansion of the interfollicular zone with vascular proliferation and increased plasma cells is observed. Representative images of hematoxylin and eosin-stained sections at 20× (A) and 100× (B) magnification are shown.
Figure 1. Histopathology of the cervical lymph node. The expansion of the interfollicular zone with vascular proliferation and increased plasma cells is observed. Representative images of hematoxylin and eosin-stained sections at 20× (A) and 100× (B) magnification are shown.
Biomedicines 12 01070 g001
Biomedicines 12 01070 g002
Figure 2. Clinical course of the patient. After the diagnosis of TAFRO syndrome, mPSL pulse therapy was initiated at 1000 mg/day for three consecutive days, followed by 60 mg/day (1 mg/kg/day) of oral PSL and 4 mg/day (0.07 mg/kg/day) of tacrolimus, targeting a trough concentration of 5–10 ng/mL. This reduced the serum CRP levels and improved thrombocytopenia and renal dysfunction. Tacrolimus treatment was continued, and the PSL was tapered.
Figure 2. Clinical course of the patient. After the diagnosis of TAFRO syndrome, mPSL pulse therapy was initiated at 1000 mg/day for three consecutive days, followed by 60 mg/day (1 mg/kg/day) of oral PSL and 4 mg/day (0.07 mg/kg/day) of tacrolimus, targeting a trough concentration of 5–10 ng/mL. This reduced the serum CRP levels and improved thrombocytopenia and renal dysfunction. Tacrolimus treatment was continued, and the PSL was tapered.
Biomedicines 12 01070 g002
Biomedicines 12 01070 g003
Figure 3. Clinical course of cardiomyopathy in TAFRO syndrome. After the sudden onset of cardiogenic shock, mPSL pulse therapy was initiated at 1000 mg/day for three consecutive days, followed by 60 mg/day (1 mg/kg/day) of oral PSL and 4 mg/day (0.07 mg/kg/day) of tacrolimus, targeting a trough concentration of 5–10 ng/mL. Serial echocardiography showed an improvement in LVEF. The levels of plasma BNP and serum troponin I were consistently reduced. Tacrolimus treatment was continued, and the PSL was tapered. BNP, brain natriuretic peptide; LVEF, left ventricular ejection fraction.
Figure 3. Clinical course of cardiomyopathy in TAFRO syndrome. After the sudden onset of cardiogenic shock, mPSL pulse therapy was initiated at 1000 mg/day for three consecutive days, followed by 60 mg/day (1 mg/kg/day) of oral PSL and 4 mg/day (0.07 mg/kg/day) of tacrolimus, targeting a trough concentration of 5–10 ng/mL. Serial echocardiography showed an improvement in LVEF. The levels of plasma BNP and serum troponin I were consistently reduced. Tacrolimus treatment was continued, and the PSL was tapered. BNP, brain natriuretic peptide; LVEF, left ventricular ejection fraction.
Biomedicines 12 01070 g003
Table 1. Adverse events associated with treatments for TAFRO syndrome.
Table 1. Adverse events associated with treatments for TAFRO syndrome.
Treatments (Suspected Drugs)Adverse Events
Monotherapy
 GlucocorticoidBacterial infection [26,27,28,29]CMV infection [3,28,29,30,31]Fungal infection [29]Tuberculosis [32]
 TocilizumabBacterial infection [29]Toxic epidermal necrolysis [33]
 Cyclosporine AHepatotoxicity [20,30,34,35,36]Renal toxicity [37]Thrombotic microangiopathy [38]
Combination therapy with glucocorticoid
 TocilizumabBacterial infection [20,39,40,41,42,43]CMV infection [37,43,44,45,46]Fungal infection [40,42]
 Cyclosporine ABacterial infection [47]CMV infection [32,47,48]Fungal infection [14,17,47]
 RituximabBacterial infection [49,50]CMV infection [50]
CMV, cytomegalovirus.
Table 2. Clinical characteristics and outcomes of patients with TAFRO syndrome treated with tacrolimus.
Table 2. Clinical characteristics and outcomes of patients with TAFRO syndrome treated with tacrolimus.
Patient1
(Present Case)		2 [20]3 [20]4 [55]5 [56]6 [38]7 [38]
Clinical characteristics
 Disease new-onset or relapseNew onsetNew onsetNew onsetNew onsetRelapseNew onsetRelapse
 SexFemaleFemaleMaleFemaleMaleFemaleMale
 Age at disease onset or relapse33681711 months574764
 Disease severity classification [21]3332242
Treatment history
Previous treatmentN.A.N.A.N.A.N.A.PSL, TAC, MMFN.A.PSL
Treatment for initial onset or relapse
mPSL/PSL+++++++
Experienced agentsTACTCZ, CsA, TACTACTCZ, TACTAC, MMFTCZ, TAC, MMF, CsATAC, CsA
Effective agentsTACTACTACTCZ, TAC−CsACsA
Adverse events−TCZ: bacterial infection
CsA: hepatotoxicity		−−−−−
Relapse-free survival>4 years>6 years>5 years>1.5 years−N.A.N.A.
TAC, tacrolimus; TCZ, tocilizumab; CsA, cyclosporine A; MMF, mycophenolate mofetil; N.A., not available.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Shirai, T.; Ichikawa, S.; Saegusa, J. Tacrolimus Treatment for TAFRO Syndrome. Biomedicines 2024, 12, 1070. https://doi.org/10.3390/biomedicines12051070

AMA Style

Shirai T, Ichikawa S, Saegusa J. Tacrolimus Treatment for TAFRO Syndrome. Biomedicines. 2024; 12(5):1070. https://doi.org/10.3390/biomedicines12051070

Chicago/Turabian Style

Shirai, Taiichiro, Shinya Ichikawa, and Jun Saegusa. 2024. "Tacrolimus Treatment for TAFRO Syndrome" Biomedicines 12, no. 5: 1070. https://doi.org/10.3390/biomedicines12051070

APA Style

Shirai, T., Ichikawa, S., & Saegusa, J. (2024). Tacrolimus Treatment for TAFRO Syndrome. Biomedicines, 12(5), 1070. https://doi.org/10.3390/biomedicines12051070

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop