Reversible lymphoproliferative disorder in systemic lupus erythematosus treated with mycophenolate mofetil: A case report and literature review

Abstract

Background

Mycophenolate mofetil (MMF) is widely used to treat systemic lupus erythematosus (SLE), particularly in cases with severe and organ-threatening complications such as lupus nephritis. However, multiple reports have documented lymphoproliferative disorder (LPD) in patients with SLE undergoing MMF therapy, predominantly developing in the central nervous system and requiring aggressive treatment, including chemotherapy, radiation, and surgery.

Case Report

We herein report the case of a 58-year-old female patient with SLE who developed cervical, hepatic hilar, and para-aortic lymphadenopathy 8 years after initiating MMF treatment. Histopathological examination of the left cervical lymph node revealed features consistent with polymorphic LPD. MMF was discontinued, and after 2 months of surveillance, the enlarged lymph nodes regressed without need for additional treatment.

Conclusion

To the best of our knowledge, this is the first reported case of MMF-associated LPD occurring outside the central nervous system in a patient with SLE, which resolved spontaneously upon MMF withdrawal. Clinicians should remain vigilant regarding the possibility of MMF-associated LPD when administering MMF to patients with SLE.

Keywords

Systemic lupus erythematosus mycophenolate mofetil lymphoproliferative disorder spontaneous regression

Background

Patients with systemic lupus erythematosus (SLE) are known to have an elevated risk of developing lymphoproliferative disorder (LPD).¹ Although the pathogenesis remains unclear, immune deficiency resulting from SLE itself or from immunosuppressive therapy is considered a potential cause of LPD. It is hypothesized that a compromised immune system leads to impaired antitumor immunity or increased susceptibility to Epstein-Barr virus (EBV) reactivation, thereby resulting in the uncontrollable proliferation of aberrant lymphocytes.^2,3 Mycophenolate mofetil (MMF) is an antimetabolite immunosuppressant widely used in the treatment of SLE, particularly lupus nephritis. However, MMF use increases the risk of LPD in patients who have undergone organ transplantation or have autoimmune diseases.⁴ In patients with SLE, multiple cases of MMF-associated LPD have been reported, all of which primarily developed in the central nervous system (CNS) and required aggressive treatment.^5–17 This report details a case of a female with SLE who developed MMF-associated LPD with generalized lymphadenopathy outside the CNS, and achieved spontaneous remission solely with the discontinuation of MMF.

Case presentation

A 58-year-old female Japanese patient with a 35-year history of SLE, complicated by lupus nephritis class Ⅳ(G)-A + class Ⅴ and lupus mastitis, visited our hospital for a routine check-up, complaining of a swelling on the left side of the neck. The patient did not suffer from fever or malaise. Her treatment consisted of 2 g of MMF and 200 mg of hydroxychloroquine (HCQ) daily for the past 8 years, during which SLE remained well controlled, with an SLE disease activity index 2000 (SLEDAI-2K) of 0/105. The patient had an anti-DNA antibody titer of <10 IU/mL (47 IU/mL at the time of SLE onset) as determined by the radioimmunoassay method, and an antinuclear antibody titer of <1:40 (1:640 with a homogenous and speckled pattern at the time of SLE onset). Before the initiation of MMF and HCQ, the patient had received immunosuppressive therapy with intravenous cyclophosphamide, mizoribine, and tacrolimus, more than 8 years prior to the development of LPD (Supplementary Figure 1).

Ultrasound examination revealed multiple enlarged bilateral cervical lymph nodes. A decline in the lymphocyte counts from 1620/μL 1 year prior to the current examination to 940/μL was noted, alongside an increase in the C-reactive protein (CRP) levels from 0.11 mg/dL to 0.73 mg/dL over the same period. Computed tomography (CT) revealed enlarged cervical, hepatic hilar, and para-aortic lymph nodes (Figure 1(a) and (b)); however, no lesions were observed on brain magnetic resonance imaging. Histological analysis of a biopsy specimen of the left cervical lymph node revealed an absence of follicular structures with notable proliferation of small to medium-sized CD3 (+) lymphoid cells and partial mingling of relatively large T cells and B cells (Figure 2(a) to (d)). EBV-encoded small RNA was negative on in situ hybridization of the lymph node specimen, and human herpes virus-8 was negative on immunohistochemical staining. Based on these findings, other iatrogenic immunodeficiency-associated LPD was diagnosed according to the World Health Organization classification, with histological features consistent with polymorphic LPD.

Figure 1.

Computed tomography findings. (a, b) Multiple enlarged lymph nodes (arrow) observed in the left cervical (a) and para-aortic (b) region at the time of onset. (c, d) Regression of the left cervical (c) and para-aortic (d) lymph nodes observed 2 months after MMF discontinuation.

Figure 2.

Histological findings of the left cervical lymph node. (a) 40x hematoxylin-eosin (HE) staining revealed an absence of follicular structures in the lymph node. (b) 200x HE staining showed a proliferation of small to medium-sized lymphoid cells and partial mingling of relatively large T cells and B cells. (c) 200x CD20 immunohistochemical (IHC) staining demonstrated the distribution of CD20 (+) B cells. (d) 200x CD3 IHC staining demonstrated the distribution of CD3 (+) T cells.

MMF therapy was discontinued, and after 2 months of close surveillance, follow-up CT revealed spontaneous regression of the cervical, hepatic hilar, and para-aortic lymph nodes (Figure 1(c) to (d)). Lymphocyte count (2200/µL) and CRP level (0.22 mg/dL) also normalized. Azathioprine was initiated 5 months after MMF discontinuation (Supplementary Figure 1). 19 months after discontinuing MMF therapy, the patient is currently receiving HCQ and azathioprine, without experiencing an SLE flare or LPD recurrence.

Discussion

LPD is a rare complication associated with SLE during treatment with MMF. Although 13 cases have been reported in the literature to date, all involved primary CNS lymphoma (Table 1).^5–17 This case represents the first report of MMF-associated LPD occurring outside the CNS in a patient with SLE. Moreover, unlike previously reported cases that required aggressive treatments, including chemotherapy, radiation, and surgery, the present case achieved spontaneous regression solely through the discontinuation of MMF therapy. These findings strongly suggest that MMF was the primary contributing factor to the development of LPD in this case.

Table 1.

Clinical characteristics of previous cases of MMF-associated LPD in patients with SLE and other autoimmune diseases.

Patient	Author and year of publication [Reference number]	Age, sex	Underlying disease	Immunosuppressive agents other than MMF	Duration of MMF	LPD lesion	Pathology	EBV	Treatment^a
Patients with SLE
1	Dasgupta et al., 2005⁵	58, F	SLE	PSL	1 year	CNS	DLBCL	Positive	Chemotherapy
2	Finelli et al., 2006⁶	42, F	SLE	PSL, AZA, CY	6 years	CNS	DLBCL	Positive	None (Died before treatment)
3	Tsang et al., 2010⁷	43, F	SLE	PSL, AZA	8 years	CNS	DLBCL	Positive	MTX + RTX, RT
4	Lai et al., 2011⁸	20, F	SLE	None	N/A	CNS	N/A	N/A	R-MPV, CYVE, ASCT
5	Svobodova et al., 2011⁹	41, F	SLE	PSL, CY, CyA	5 years	CNS	DLBCL	Negative	R-MPV, RT
6	Tse et al., 2014¹⁰	39, F	SLE	PSL	11 years	CNS	DLBCL	Positive	Surgery, RT, everolimus, RTX
7	Turno-Kręcicka et al., 2016¹¹	44, F	SLE	PSL, chloroquine	14 months	CNS	B-cell lymphoma	N/A	Chemotherapy
8	Boddu et al., 2017¹²	57, F	SLE	IVCY, PSL, HCQ	N/A	CNS	DLBCL	N/A	MTX
9	Balci et al., 2017¹³	56, F	SLE	PSL, HCQ	2 years	CNS	DLBCL	Negative	MTX + RTX + temozolomide
10	Su et al., 2018¹⁴	39, F	SLE	PSL, HCQ, MTX, CyA	1.5 years	CNS	DLBCL	Positive	Surgery, MTX + RTX + cytarabine, ASCT
11	Garcia-Grimshaw et al., 2020¹⁵	40, F	SLE	N/A	N/A	CNS	N/A	N/A	N/A
12	Ichikawa et al., 2021¹⁶	34, F	SLE	PSL, TAC, IVCY, mesalazine	14 months	CNS	DLBCL	Positive	Surgery, RT, MTX + RTX
13	Sakairi et al., 2022¹⁷	41, F	SLE	PSL, IVCY	10 months	CNS	DLBCL	Positive	R-MPV
14	Present case	58, F	SLE	HCQ	8 years	Lymph node	Polymorphic LPD	Negative	None
Patients with other autoimmune disease
15	Waldman et al., 2004¹⁸	46, F	DM	PSL, MTX	1.5 years	CNS	B-cell lymphoma	Positive	DEX
16	Vernino et al., 2005¹⁹	88, F	MG	PSL	3 years	CNS	DLBCL	Positive	RTX
17	O’Neill et al., 2007²⁰	58, F	CNSV	PSL, HCQ, AZA	5 years	CNS	Polymorphic LPD	Positive	DEX + RTX
18	O’Neill et al., 2007²⁰	65, M	RP	PSL, AZA	11 months	CNS	DLBCL	Positive	DEX + RTX
19	O’Neill et al., 2007²⁰	57, F	DM	PSL, AZA	8 months	CNS	Polymorphic LPD	Positive	DEX + RTX
20	Dubal et al., 2009²¹	69, F	MG	PSL	6 years	Mons pubis	T-cell LPD	Positive	None
21	Adams et al., 2010 ²²	42, F	AIH	None	3 years	Mouth	Hodgkin-like lymphoma	Positive	RTX
22	Li et al., 2019²³	63, M	DM	PSL, CY	3 months	Lung	DLBCL	N/A	R-CHOP
23	Chatterjee et al., 2020²⁴	51, F	SSc	None	5 years	CNS	B-cell lymphoma	Positive	MTX + RTX
24	Shrestha et al., 2020²⁵	81, F	EGPA	PSL, AZA	6 years	CNS	B-cell lymphoma	Positive	RTX
25	Kobe et al., 2021²⁶	76, F	DM	PSL, TAC	4 years	Lung	DLBCL	Positive	None
26	Taliaferro et al., 2021²⁷	74, M	SSc	None	N/A	Mouth	Polymorphic LPD	Positive	Surgery, MMF reduction

^aMMF was discontinued and not rechallenged unless otherwise specified in the reported cases.

AIH, autoimmune hepatitis; ASCT, autologous stem cell transplantation; AZA, azathioprine; CNS, central nervous system; CNSV, central nervous system vasculitis; CY, cyclophosphamide; CyA, cyclosporin A; CYVE, cytarabine + etoposide; DEX, dexamethasone; DLBCL, diffuse large B-cell lymphoma; DM, dermatomyositis; EGPA, eosinophilic granulomatosis with polyangiitis; F, female; HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; LPD, lymphoproliferative disorder; M, male; MG, myasthenia gravis; MTX, methotrexate; N/A, not available; PSL, prednisone or prednisolone; R-CHOP, rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone; R-MPV, rituximab + methotrexate + procarbazine + vincristine; RP, relapsing polychondritis; RT, radiation therapy; RTX, rituximab; SSc, systemic sclerosis; TAC, tacrolimus.

Similar cases of MMF-associated LPD have been reported in 12 patients with autoimmune diseases other than SLE (Table 1).^18–27 Among these, five cases involved non-CNS LPDs occurring in the lung, mouth, and mons pubis.^{21–23,26,27} Three cases exhibited a pathological feature consistent with polymorphic LPD,^20,27 and one case was identified as T-cell LPD.²¹ Spontaneous remission was achieved in two cases solely through MMF withdrawal,^21,26 whereas one case was administered only dexamethasone in addition to MMF discontinuation.¹⁸

Histological analysis of the present case revealed a polymorphic LPD pattern; however, EBV-encoded small RNA were not detected, unlike previous cases of MMF-associated LPD with SLE, which predominantly involved EBV-related diffuse large B cell lymphomas (DLBCL).¹⁷ Among the 13 previously reported cases, 11 were identified as DLBCL, while the pathology of the remaining two cases was unspecified. EBV status was reported as positive, negative, and not mentioned in seven, two, and four cases, respectively. Interestingly, a pathological feature of polymorphic LPD has been associated with a favorable prognosis in patients with rheumatoid arthritis (RA) who developed methotrexate (MTX)-associated LPD.²⁸ This observation aligns with the outcome of the current case, which demonstrated self-remission following the withdrawal of MMF therapy.

In the current case, a gradual decrease in the lymphocyte counts and an increase in CRP levels were observed before LPD development, both of which promptly resolved after the discontinuation of MMF. A similar trend was reported by Inui et al. in patients with RA who developed MTX-associated LPD, where early lymphocyte recovery 2 weeks after MTX withdrawal predicted a spontaneous regression of LPD at 1 month.²⁹ In the present case, the lymphocyte count increased from 940/μL to 1870/μL 1 month after MMF withdrawal, and to 2200/μL after 2 months. Lymphadenopathy regressed 1 month after the discontinuation of MMF, with confirmation by CT imaging 2 months later. These findings suggest that the observation made by Inui et al. may also be relevant to MMF-associated LPD; however, further studies are required to confirm this hypothesis.

Conclusions

Clinicians should be aware of the possibility of LPD occurring in patients with SLE receiving MMF. The present case demonstrated that MMF-associated LPD can occur in the lymph nodes outside the CNS. When MMF-associated LPD is suspected, the possibility of spontaneous regression should be considered, as this may help avoid unnecessary and potentially harmful treatment, particularly when polymorphic LPD is histologically diagnosed and recovery of the lymphocyte counts is observed following MMF withdrawal.

Supplemental Material

Supplemental Material - Reversible lymphoproliferative disorder in systemic lupus erythematosus treated with mycophenolate mofetil: A case report and literature review

Supplemental Material for Reversible lymphoproliferative disorder in systemic lupus erythematosus treated with mycophenolate mofetil: A case report and literature review by Hiroto Tomoda, Muneo Nakaya, Seiichiro Nakabeppu, Hiroaki Miyoshi, Koichi Ohshima and Yuji Miyoshi in Lupus

Footnotes

Author’s Note

A part of this case report was presented in an oral session at the 690^th Kanto Region Meeting of the Japanese Society of Internal Medicine on October 14, 2023.

Acknowledgments

We would like to thank Editage () for English language editing.

Authors’ contributions

Y.M., H.T., and M.N. contributed to the patient’s care. S.N, H.M, and K.O. reviewed the pathological findings. Y.M. conceived the study. H.T. prepared the manuscript. All authors critically reviewed and revised the manuscript for intellectual content.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical statement

ORCID iDs

Hiroto Tomoda

Yuji Miyoshi

Data Availability Statement

The clinical data used and/or analyzed during the current case report are available from the corresponding author upon reasonable request.*

Supplemental Material

Supplemental material for this article is available online.

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