TAFRO-like Symptoms in a Sjögren's Syndrome Patient with HTLV-1 Infection

Abstract

A 58-year-old woman was admitted to our hospital with anasarca and generalized lymphadenopathy. Laboratory data showed serum creatinine 1.48 mg/dL, C-Reactive Protein 2.38 mg/dL, platelet 102,000/μL, and anti-SS-A antibodies. A lymph node biopsy revealed a regressed germinal center and hypervascularization in the interfollicular area. The patient was diagnosed with TAFRO-like symptoms occurring with Sjögren's syndrome and human T-cell leukemia virus type 1 (HTLV-1) infection, and 80 mg of methylprednisolone and tocilizumab 8 mg/kg biweekly were initiated. Her body weight decreased from 59.4 to 41 kg, and pleural effusion disappeared 8 weeks later. This case suggests that TAFRO-like symptoms may occur in patients with Sjögren's syndrome with HTLV-1 infection.

Introduction

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus isolated in 1980 (1). It causes adult T-cell leukemia (ATL) (2) as well as autoimmune conditions, such as HTLV-1-associated myelopathy (HAM) and HTLV-1-associated uveitis (3).

Sjögren's syndrome (SS) is a well-known autoimmune disease characterized by sicca symptoms (4). A recent study has suggested that HTLV-1 contributes to the development of SS (5). An epidemiological study revealed a high prevalence of anti-HTLV-1 antibodies among patients with SS in an HTLV-1-endemic area (6).

Thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) (TAFRO) syndrome was originally described in Japanese patients by Takai et al. (7). It is a systemic inflammatory disease categorized as a subtype of idiopathic multicentric Castleman disease (iMCD). TAFRO syndrome was recently proposed to develop without iMCD or with other comorbidities such as infection, autoimmune disease, and malignant disease (8). Many cases of SS or anti-SS-A antibody positivity have recently been reported in patients diagnosed with TAFRO (9,10), and some researchers have hypothesized that TAFRO syndrome is a severe manifestation of SS (9). However, there is currently no evidence suggesting that HTLV-1 contributes to the development of TAFRO-like symptoms.

We herein report a case of SS with TAFRO-like symptoms and HTLV-1 and discuss the relationship between HTLV-1 and TAFRO syndrome.

Case Report

A 58-year-old woman was admitted to our hospital with a 1-month history of anasarca and orthopnea. The patient was initially treated for heart failure. However, she was referred to the Department of General Internal Medicine because of diuretic resistance, generalized lymphadenopathy, and elevated serum levels of the soluble IL-2 receptor. She had sicca symptoms and fatigue but not arthralgia. Her medical history included a bone fracture of the left wrist, heart valve disease, and atrial or ventricular septal defect with no known details. She had no family history of rheumatological diseases. She and her parents were from Tokyo, an area of Japan where the prevalence of HTLV-1 was reported to be 0.65% in middle-aged women (11). She had no allergies, was not regularly receiving medication, and did not drink or smoke.

During the consultation, body temperature was 37.7°C, blood pressure was 128/75 mmHg, heart rate was 101 beats per minute, respiratory rate was 20 breaths per minute, and oxygen saturation was 98% while breathing with 2 L of oxygen. Her height and weight were 144 cm and 58.8 kg, respectively. A physical examination revealed a dry tongue, enlarged parotid gland and cervical lymph nodes, edema below the chest, and decreased breathing sounds during auscultation.

Non-enhanced computed tomography showed splenomegaly, enlargement and calcification of the parotid gland, and cervical, mediastinal, intraperitoneal, and inguinal lymphadenopathies. Pleural and ascitic fluid, as well as subcutaneous edema below the chest, were noted (Fig. 1). Laboratory data were as follows: PLT 10.2×10⁴/μL (15.8-34.8), creatinine (Cr) 1.48 mg/dL (0.46-0.79), γ-GTP 167 U/L (9-32), alkaline phosphatase 626 U/L (38-113), lactate dehydrogenase 259 U/L (124-222), CRP 2.38 mg/dL (0.00-0.14), IgG 1,738 mg/dL (820-1,740), soluble interleukin-2 receptor (sIL-2R) 3,060 U/mL (157-474), IgG4 22.4 mg/dL (11-121), antinuclear antibody (Speckled) 40, rheumatoid factor 121 U/mL (0.0-15), anti-SS-A (FEIA) antibody ≥240 U/mL (＜7), anti-SS-B antibody (FEIA) 12.8 U/mL (＜7), negative for the human immunodeficiency virus (HIV) antigen/antibody, ATLV ≥256 (＜16), and positive serum Western blotting (for the viral proteins of HTLV-1) for p19, p24, gp46, and gp21. The other data are presented in (Table 1).

Figure 1.

Chest X-ray showed pleural effusion bilaterally. Non-enhanced CT showed splenomegaly and cervical, mediastinal, intraperitoneal, and inguinal lymphadenopathy. Pleural and ascitic fluid as well as subcutaneous edema below the chest were also noted.

Table 1.

Laboratory Data on Admission.

Complete blood count and coagulation system test			Blood chemistry and immunological tests
WBC	7	×103/μL	TP	6.1	g/dL	CH50	19.4	CH50/mL
Neu	61.6	%	Alb	2.6	g/dL	C3	59	mg/dL
Lymph	34.4	%	GLU	97	mg/dL	C4	4	mg/dL
Mono	5.8	%	BUN	40	mg/dL	IgG	1,738	mg/dL
Eosi	0.9	%	Cr	1.48	mg/dL	IgA	158	mg/dL
At.lym	0.5	%	UA	11.9	mg/dL	IgM	358	mg/dL
Hb	9.9	g/dL	Na	144	mmol/L	M protein	(-)
MCV	92.1	fL	K	5.1	mmol/L	Cryoglobulin	(-)
PLT	10.2	×104/μL	Cl	113	mmol/L	sIL-2R	3,060	U/mL
PT-INR	1.05		CK	35	U/L	IgG4	22.4	mg/dL
APTT	33.5	s	Ca	8.2	mg/dL	ANA	40×
D-dimer	10.8	μg/mL	AST	24	U/L	Anti-ds-DNA antibody	<10	IU/mL
Urinalysis			γ-GT	167	U/L	RF	121	U/mL
Gravity	1.108		ALP	626	U/L	Anti-SS-A antibody	≥240	U/mL
pH	55		LD	259	U/L	Anti-SS-B antibody	12.8	U/mL
Protein	1+		CRP	2.38	mg/dL	ACE	11.6	U/L
WBC	20-29	/HPF	Ferritin	572	ng/mL	T-spot	(-)
RBC	1-4	/HPF	TSH	13.04	µIU/mL	HIV antigen/antibody	(-)
Pleural effusion test			FT4	1.1	ng/dL	CMV-IgM	0.86
TP	2.6	g/dL	25-Vit D	<4.0	ng/mL	ATLV	≥256
Alb	13	g/dL	NT-proBNP	9,083	pg/mL	Serum Western blotting	positive for p19, p24,
LDH	93	U/L	ESR	24	mm/h	for HTLV-1 viral	gp46, and gp21
TG	21	mg/dL				proteins
Cell count	175	/μL

The Saxon test (0.2 g per 2 min) and labial biopsy (＞50 lymphocytes/plasma cells infiltrating around the ducts within salivary gland lobules, adipose infiltration, acinar atrophy, and mild dilatation of ducts) were positive. Salivary gland ultrasonography revealed severe sialadenitis as hypoechoic areas, fatty changes, fibrosis, and Power Doppler signals [Gray Scale 3, Power Doppler signal 3 as a grading system of the Outcome Measures in Rheumatology Clinical Trials; OMERACT (12)] in both parotid glands (Fig. 2).

Figure 2.

Non-enhanced computed tomography showed the enlargement and calcification of the parotid gland. Salivary gland ultrasonography showed hypoechoic areas, fatty changes, fibrosis, and power Doppler signals in both parotid glands.

A bone marrow biopsy revealed a normal cellular bone marrow with increased megakaryocytes and reticulin fibrosis and no malignancy. A lymph node biopsy revealed an atrophic germinal center and hypervascularization in the interfollicular area. Hyalinization of the vessel walls, prominent plasmacytes, IgG4+ cells, and malignancy were not observed in the lymph nodes. Polymerase chain reaction of the lymph nodes for HTLV-1 provirus was positive (Fig. 3). A flow cytometric analysis of the lymph nodes and bone marrow revealed a normal kappa/lambda light-chain ratio and no evidence of abnormal cell infiltration, such as prominent CD8+ T cells or malignant lymphoma.

Figure 3.

Bone marrow biopsy. Hematoxylin and Eosin (H&E) staining, low power field (a), silver impregnation stain, low power field (b). Bone marrow biopsy showed normal cellular bone marrow with increased megakaryocytes and reticulin fibrosis. Biopsy of lymph nodes. H&E staining, low power field (×20) (c). Lymph node biopsy showed an atrophic germinal center and hypervascularization in the interfollicular area.

The patient was diagnosed with SS, HTLV-1 infection, and TAFRO-like symptoms. Administration of 80 mg of methylprednisolone and 8 mg/kg of tocilizumab (TCZ), an anti-interleukin-6 (IL-6) drug, was initiated on days 18 and 26, respectively. The changes in the serum and pleural fluid levels of IL-6 and vascular endothelial growth factor (VEGF) are shown in (Table 2).

Table 2.

Transition of IL-6 and VEGF in Serum and Pleural Effusion.

	Day 17	Day 31	Day 45
Serum IL-6 (pg/dL)	24.2	145	303
Serum VEGF (pg/dL)	285	310
Pleural effusion IL-6 (pg/dL)	2,330
Pleural effusion VEGF (pg/dL)	262

On day 31, the Cr and CRP levels improved to 0.67 and 0.38 mg/dL, respectively. The PLT also increased from approximately 100,000 to 150,000/μL. Her body weight decreased from 59.4 to 41 kg, and pleural effusion disappeared on day 71 (Fig. 4). Her serum VEGF level increased from 285 to 310 pg/dL during the treatment course, despite the disappearance of pleural effusion and improvements in CRP and Cr levels. She was discharged on day 71, and there has been no recurrence 20 months after discharge.

Figure 4.

The administration of 80 mg methyl prednisolone and 8 mg/kg TCZ biweekly was initiated on days 18 and 26, respectively. On day 31, creatinine and CRP improved to 0.67 and 0.38 mg/dL, respectively. platelet also increased from approximately 100,000 to 150,000/μL. Body weight decreased from 59.4 to 41 kg and pleural effusion disappeared on day 71. mPSL: methylprednisolone, TCZ: tocilizumab, BW: body weight, IV: intravenous injection, po: peros

Discussion

This is the first case report of TAFRO-like symptoms occurring in an SS patient infected with HTLV-1. HTLV-1 is endemic to southern Japan, the Caribbean, parts of Africa, the Middle East, South America, the Pacific Melanesian islands, and Papua New Guinea (13). In Japan, the number of HTLV-1 carriers is estimated at 534,000 (14). In addition, approximately 1 in 1 million individuals in Japan is affected by TAFRO syndrome (15), and the number of patients with SS is estimated to be 68,483 (16).

Although the prevalence of TAFRO-like symptoms occurring with SS and HTLV-1 remains unclear, HTLV-1 is one of the speculated etiologies of SS, and a recent meta-analysis of epidemiological studies revealed that HTLV-1 was associated with increased odds of developing SS (odds ratio 3.25, 95% confidence interval 1.85-5.70) (17). Among the previous case series on TAFRO-like symptoms occurring with SS (9,10), none focused on HTLV-1; however, this may have been because it was not described or measured. Therefore, the present case suggests that HTLV-1 is a trigger for TAFRO-like symptoms, as well as SS.

In 7 case reports of TAFRO syndrome (6 cases were positive for anti-SS-A antibodies) in Japan (9), the median age of patients was 48 [interquartile range (IQR) 41-53] years old, Cr 1.7 (IQR: 1.5-2.3) mg/dL, PLT 3.8 (IQR: 2.2-6.4)×10⁴/μL, CRP 10.2 (IQR: 6.8-21.4) mg/dL, and sIL-2R 918 (IQR: 473-1,250) U/mL. According to clinical data on TAFRO syndrome from the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome registry (UMIN000011809) from 89 collaborating centers in Japan (18), the serum level of sIL-2R was 1,598 (IQR: 1.060-2,082) U/mL in the second-line treatment group (n=43) and 1,927 (IQR: 1,432-2,521) U/mL in the corticosteroid-only group (n=19). Based on these findings, the activity of lymphocytes appeared to be high in the present case (sIL-2R 3,060 U/mL). No lymphoma was detected in the lymph nodes, lips, or marrow. Therefore, an elevated serum level of sIL-2R may be a clinical indicator of HTLV-1 infection in patients with SS and TAFRO-like symptoms.

The serum level of VEGF in our patient increased from 285 to 310 pg/dL during the treatment course despite the disappearance of pleural effusion, improvements in CRP and Cr levels, and no recurrence in the 20 months after discharge. A previous case report (19) of a patient with TAFRO syndrome noted exacerbation of anasarca, CRP, and Cr with an increase in the serum level of VEGF. The production of VEGF by HTLV-1-infected cells has been reported (20), and further studies are needed to establish whether or not elevated serum VEGF levels are associated with disease severity in cases of TAFRO-like symptoms with HTLV-1 infection.

Furthermore, the serum level of IL-6 was 24.2 pg/mL in the present case, which was higher than that in 10 previous case reports of TAFRO-like symptoms occurring with SS [12.2 (5-18) pg/mL; 7 cases from Japan] (10). As discussed above, HTLV-1 causes autoimmune conditions such as HAM and HTLV-1-associated uveitis (3). Three types of dysregulation of the cytokine network have been reported during HTLV-1 infection and HTVL-1-associated disease: asymptomatic, proinflammatory, or immunosuppressive (21). Tax, a viral protein, activates NF-κB (22). In the pro-inflammatory state, pro-inflammatory cytokines (IFN-γ, IL-1, TNF-α, and IL-6) are produced by HTLV-1-infected cells (21,23,24). A previous study proposed that HTLV-1 may trigger SS by directly infecting the salivary glands and inducing chronic inflammation rather than cytokine dysregulation and autoantibody production (5). However, VEGF, which is associated with the pathophysiology of TAFRO syndrome, is also produced by HTLV-1-infected cells (20). These mechanisms may explain the relationship between HTLV-1 and TAFRO syndrome; however, further studies are required.

Another perspective may provide insights into the relationship between HTLV-1 and TAFRO syndrome. An important differential diagnosis is diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by bilateral salivary gland enlargement, sicca symptoms, lymphadenopathy, and organomegaly associated with polyclonal CD8+ T-cell organ infiltration in patients with HIV infection (22,25). The bilateral parotid gland enlargement, sicca symptoms, lymphadenopathy, and organomegaly in the present case were similar to the symptoms of DILS; however, the present case was negative for HIV antigens/antibodies. A previous study that compared tissues from the minor salivary glands of HTLV-1 seropositive patients and SS patients revealed a higher number of CD8+ T cells in the HTLV-1 group and CD20+ B cells than in the SS group (26). A biopsy of the enlarged parotid gland was not performed in our patient; therefore, the accumulation and comparison of HTLV-1 cases with TAFRO-like symptoms and HIV with DILS are needed.

The effects of immunosuppression on the natural history of HTLV-1 remain unclear (27). Careful utilization of immunosuppressants and surveillance of HTLV-1-infected patients are recommended because of the risk of HTLV-1-related diseases, such as HAM (27,28); however, TCZ does not affect HTLV-1-infected cells in vitro (29). No symptoms of HTLV-1-related disease were detected in the present case.

Conclusion

We encountered a case of TAFRO-like symptoms occurring with SS and HTLV-1 infection. These results suggest that HTLV-1 is associated with the onset of TAFRO-like symptoms as well as SS. Elevated serum levels of VEGF despite the trend of clinical improvement may be a clinical key to HTLV-1 infection among patients with TAFRO-like symptoms and SS. Further investigations are needed to reveal the epidemiology, pathogenesis, and outcomes of TAFRO-like symptoms occurring with SS and HTLV-1 infection.

Informed consent for the publication of the details of this case was obtained from the patient.

The authors state that they have no Conflict of Interest (COI).