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May 11, 2012 - Abstract We report a case of dermatomyositis (DM) and hemophagocytic lymphohistiocytosis (HLH) complicated by central nervous system ...
Mod Rheumatol (2013) 23:386–392 DOI 10.1007/s10165-012-0661-6

CASE REPORT

Hemophagocytic lymphohistiocytosis complicated by central nervous system lesions in a patient with dermatomyositis: a case presentation and literature review Hiroyuki Yamashita • Yuko Matsuki • Arisa Shimizu • Makoto Mochizuki • Yuko Takahashi • Toshikazu Kano Akio Mimori



Received: 7 March 2012 / Accepted: 20 April 2012 / Published online: 11 May 2012 Ó Japan College of Rheumatology 2012

Abstract We report a case of dermatomyositis (DM) and hemophagocytic lymphohistiocytosis (HLH) complicated by central nervous system (CNS) lesions and review eight literature cases of DM and HLH. A 17-year-old woman, admitted to our hospital because of severe muscle weakness and high fever, was diagnosed with DM based on elevated serum levels of muscle enzymes and a typical skin rash. Pancytopenia, high serum ferritin and soluble interleukin (IL)-2 receptor, and hepatosplenomegaly were also noted. Bone-marrow examination was negative for hemophagocytosis. Steroid therapy combined with immunoglobulin i.v. was ineffective against the DM, pancytopenia, hepatic dysfunction, and hyperferritinemia. On the 27th hospital day, seizures and acute respiratory failure occurred. In the course of improving muscle enzyme levels after starting adjunctive treatment with cyclosporine, the patient suffered disturbed consciousness, dyskinesia, and tremor. Brain magnetic resonance imaging (MRI) revealed T2 hyperintense lesions in the pons. Additional cyclophosphamide pulse therapy successfully decreased serum ferritin. Unfortunately, the diffuse alveolar damage (DAD) confirmed by biopsy progressed and the patient died. Autopsy findings revealed DAD throughout both lungs, HLH liver lesions, and a hemorrhagic necrotic lesion of the pons in the brain. Even when pathological examination yields no findings of

H. Yamashita (&)  Y. Matsuki  A. Shimizu  Y. Takahashi  T. Kano  A. Mimori Division of Rheumatic Diseases, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan e-mail: [email protected] M. Mochizuki Department of Pathology, Hospital, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan

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hemophagocytosis, it is important to comprehensively and rapidly diagnose HLH based on the clinical picture. Because DM complicated by HLH may be associated with abnormal production of cytokines and systemic autoimmune responses, it may be necessary to immediately administer additional immunosuppressive therapy. We describe and discuss the extraordinary, severe form of DM in our patient, along with cases in the literature. Keywords Dermatomyositis  Hemophagocytic lymphohistiocytosis  Central nervous system  Diffuse alveolar damage  Immunosuppressive therapy

Introduction Hemophagocytic syndrome (HPS), also known as secondary hemophagocytic lymphohistiocytosis (HLH) [1], reflecting cytokine storms [2], is a rare disorder of the mononuclear phagocytic system characterized by systemic proliferation of nonneoplastic histiocytes engaged in abnormal phagocytosis of hematopoietic cells [3]. Common manifestations include high fever, pancytopenia, hepatosplenomegaly, and disseminated intravascular coagulopathy. Although HPS has been associated with autoimmune disease, few case reports have been published describing HPS in patients with dermatomyositis (DM) [4–8]. Here we report a case of severe HPS complicated by central nervous system (CNS) lesions in an adolescent patient with DM.

Case report A 17-year-old woman was admitted with fever, muscle weakness, and associated myalgia and polyarthritis of

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about 2 months’ duration. She also had cutaneous signs: a heliotrope rash and Gottron’s sign, nail-fold lesions, and erythematous eruptions on her elbows, hands, and feet. After admission, her body temperature rose to 38.8 °C. On physical examination, hepatosplenomegaly and proximal muscle weakness were noted. A peripheral blood cell count and biochemistry revealed the following: aspartate aminotransferase (AST) 1,512 IU/L; alanine aminotransferase (ALT) 642 IU/L; lactate dehydrogenase (LDH) 1,046 IU/ L; alkaline phosphatase (ALP) 103 U/L; C-reactive protein (CRP) 0.01 mg/dl; and creatine kinase (CK) 1,094 IU/ L. White blood cell (WBC) count was 1.2 9 103/ml with 77 % neutrophils, 20 % lymphocytes, hemoglobin (Hb) 12.1 g/dl (normocytic), platelets (Plt) 66 9 103/ml, and platelet-associated immunoglobulin (PA-IgG) 19.7 ng/ 107 cells. Serum ferritin and soluble interleukin-2 receptor (sIL-2R) were increased at 4,172 ng/ml and 2,046 IU/L, respectively. Serum immunoglobulins and complement were normal. Polymerase chain reaction (PCR) analyses showed no evidence of recent infection with Epstein–Barr virus (EBV), cytomegalovirus (CMV), varicella zoster virus (VZV), or human herpesvirus 6 (HHV-6) or herpes simplex virus (HSV). Serological studies were performed for EBV and CMV. For EBV, IgM antibody against the viral capsid antigen (VCA IgM), IgG antibody against VCA (VCA IgG), and IgG antibody against EBV nuclear antigen IgG (EBNA IgG) were negative, indicating the pattern of a noninfected person; IgM antibody against CMV was negative, meaning that recent CMV infection was unlikely. Natural killer (NK)-cell activity [1.0 % (normal 8.9–29.5 %)] was decreased. Although slightly positive for antinuclear antibodies (1:80), the patient was negative for specific antibodies, including anti-Jo-I antibody. Specifically, other tests for antibodies to doublestranded DNA, small nuclear ribonucleoprotein (snRNP), SSA and SSB antibodies, anticardiolipin/beta2-glycoprotein I (CL-b2GPI), and mitochondria M2 were negative; tests for perinuclear antineutrophil cytoplasmic antibodies (PANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (CANCA) were also negative. Magnetic resonance imaging (MRI) revealed extensive T2 hyperintense lesions and enhancement in both femoral muscles. Chest computed tomography (CT) revealed consolidation in the left S6 segment, suggesting interstitial pneumonia (IP). Based on increased creatine phosphokinase (CPK) levels, muscle weakness predominantly in the proximal muscles, typical myositis findings on thigh MRI, and typical rash, DM complicated by IP was diagnosed. To treat the DM, steroid pulse therapy was instituted on the ninth hospital day. Prednisolone (PSL) 50 mg/day was administered as a posttreatment. As the CPK level did not improve (1,011 IU/L on the 19th hospital day), immunoglobulin i.v. was started on the 19th hospital day; however,

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there was little improvement. By the 26th day, the patient continued to show pancytopenia, hepatic dysfunction (CK 1,100 IU/L, WBC 2.82 9 103/ml, Hb 8.6 g/dl, Plt 11.2 9 104/ml, AST 721 IU/L, ALT 292 IU/L, and LDH 1,069 IU/L). On the 27th hospital day, three seizures occurred suddenly, accompanied by acute respiratory failure. Mechanical ventilation was instituted. On chest CT, consolidation and ground-glass opacity/attenuation scattered throughout both lungs were seen. Bronchoalveolar lavage (BAL) was negative for Pneumocystis jirovecii pneumonia (PCP)-PCR and CMV-PCR. Spinal fluid examination and brain MRI revealed no abnormality, and spinal fluid was negative for EBV, CMV, and HSV/VZVPCR. Fever, splenomegaly, cytopenia, high serum LDH, ferritin, and sIL-2R, and decreased NK cells were recognized, and we diagnosed HLH associated with DM as the cause of the convulsions based on the diagnostic criteria for HLH by Henter et al. [9]. After aggressive treatment with continuous intravenous infusion of dexamethasone (DEXA) 10 mg/day and cyclosporine (CsA) 100 mg/day on the 27th hospital day, CPK decreased to 728 IU/L on the 29th hospital day and to 300 IU/L on the 33rd hospital day. However, the patient’s consciousness diminished, and dyskinesia, primarily of the tongue; tremor in the left upper limb; and oculomotor nerve palsy were evident starting on the 31st hospital day. Brain MRI performed on the 33rd hospital day revealed mild T2 hyperintense lesions, local swelling, and enhancement in the pons, suggesting brainstem lesions due to HLH (Fig. 1a). On the same day, DEXA 100 mg/day for 3 days was instituted to treat CNS issues. On the following day, a cyclophosphamide pulse (IVCY) was administered. Subsequently, ferritin levels showed significant improvement and decreased to 828 ng/ml on the 38th hospital day. A transbronchial lung biopsy performed on the 39th hospital day revealed diffuse alveolar damage (DAD). Moreover, bloody fluid was collected by BAL, and the possibility of pulmonary hemorrhage was suggested. At autopsy, pulmonary hemorrhage was noted in eight of nine HLH cases and DAD was seen in six [10]; thus, it was suspected that the lung findings were due to the HLH. On the 46th hospital day, mediastinal emphysema occurred. The patient died on the 53rd hospital day. At autopsy, a 1 9 1-cm area of hemorrhagic necrosis was seen in the centre of the pons (Fig. 1b). The lesion was composed of hemorrhage, many spheroids, and foamy macrophage infiltration (Fig. 1c–e). Immunohistochemically, no cells were positive for parvovirus or CMV. EBV-encoded ribonucleic acid in situ hybridization (EBER-ISH) was negative. In the midbrain, microscopic necrotic foci without hemorrhage were found. No other CNS lesions were identified. DAD with a hyaline membrane was found throughout both lungs. CMV and P. jirovecii were not identified in the lungs. The liver

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Fig. 1 Central nervous system lesion in the pons. a A mild T2 hyperintense lesion and mild local swelling were observed on the left side of the pons (arrow). Infiltration of hemophagocytic lymphohistiocytosis (HLH) into central nerves was suspected. b At autopsy, a 1 9 1-cm necrotic lesion with hemorrhage was found in the center of

the pons (arrow). c Kluver–Barrera (K–B) stain showed disappearance of the myelin sheath in the lesion (arrow). d, e The lesion was composed of hemorrhage, many spheroids, and foamy macrophage infiltration (arrow) [hematoxylin and eosin (H&E) stain 9100 (d), 9400 (e)]

(1,600 g) showed marked steatosis, infiltration of moderate ceroid-laden macrophages in the sinusoids, few hepatocytic necrotic foci, and little lymphocytic infiltration (Fig. 2a). Liver histology was compatible with liver lesions of HPS [10]. Splenomegaly (150 g) was seen, and the spleen contained numerous erythrophagocytosing macrophages (Fig. 2b), confirming the diagnosis of hemophagocytic syndrome. The clinical course is presented in Fig. 3.

DM complicating CNS lesions; our patient is the first such reported case. Kumakura et al. [2, 11] proposed a disease entity called autoimmune-associated hemophagocytic syndrome (AAHS). The pathogenesis of AAHS could be explained by autoantibody-mediated [2], immune-complex-mediated [11], or cytokine-mediated mechanisms [12]. First, autoantibodies may react to blood cells, resulting in hemophagocytosis by stimulated histiocytes through the Fcc receptor, primarily in bone marrow [2]. Second, blood cells sensitized by immune complexes may be phagocytosed by histiocytes via complement–receptor interactions. Finally, uncontrolled production of inflammatory cytokines may activate histiocytes. Whereas the commonly reported pathogenesis of diseases caused by the primary immune disorders such as SLE and mixed connective tissue disease involves the second mechanism [11], adultonset Still disease is often caused by the third mechanism

Discussion In autoimmune diseases, a combination of HPS/HLH with mainly systemic lupus erythematosus (SLE) is occasionally observed [11]; however, the combination with DM is extremely rare. Only eight cases have been reported [4–8]. Moreover, there is no report of HPS/HLH associated with

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Fig. 2 Autopsy findings of the liver and spleen. a Hepatic histology showed a moderate infiltration of ceroid-laden macrophages in the sinusoids, few hepatocytic necrotic foci, some lymphocytic infiltration, and mild steatosis (periodic acid–Schiff diastase stain, 9400).

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b The spleen had foamy macrophage infiltration and several erythrophagocytotic macrophages (arrow) (hematoxylin and eosin stain, 9400)

Fig. 3 Clinical course

[12]. As serum sIL-2R was high in our patient, and serum PA-IgG was normal and hypocomplementemia was not observed, we suggest a cytokine-mediated mechanism as the main cause of HPS. However, autoantibodies, such as antigranulocyte antibody, were not measured. Therefore, the possibility of the involvement of macrophage activation via an autoantibody-mediated mechanism remains.

Table 1 shows case reports of DM-associated HPS/HLH and the pathogenic mechanisms underlying these disorders [4–8]. The case reported by Sugihara et al. [4] supports the third mechanism, because the levels of immune complex C1q (IC-C1q), complement factors, and PA-IgG were normal whereas those of macrophage-colony-stimulating factor (M-CSF), tumour necrosis factor-a (TNF-a), and sIL-2R were elevated. The case reported by Yasuda et al.

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123

60 M

83 M

48 F

14 M

16 M 36 M

50 M

86 M

17 F

1

2

3

4

5 6

7

8

9

1,094

3,877

5,604

122 11,338

26

142

3,208

1,527

CK

2,046

5,329

585

2,796 2,854

765

Normal

Normal

3,831

Ferritin (ng/ml)

N/A

Positive

ND

ND

N/A

ND

IC-C1q

0.01

1.6 ± 0.5

0.24 (ESR 28)

N/A

0.25

0.7

CRP (mg/dl)

N/A for others

sIL-2R

sCX3CL1

sIL-2R M-CSF

neopterin

sIL-2R

IFN-c

N/A

N/A

M-CSF, TNFa, sIL-2R

Cytokine

Anti-Jo-I antibody: negative

Anti-Jo-I antibody: negative

PA-IgG

PA-IgG

anti-Mi2

ANA

ND

Autoantibody

? (spleen)

?

? (bone marrow)

? (bone marrow)

? (bone marrow)

? (bone marrow)

HPS finding

Hypercytokinemia autoantibody-mediated

Hypercytokinemia Immune complex

Hypercytokinemia autoantibody

Autoantibody

Unknown

Hypercytokinemia

Assumed mechanism

IVCY 1,000 mg

CyA 100 mg.div/ day

mPSL pulse, PSL 50 mg/day

Immunosuppressants

Steroid pulse IVIG

IVIG

CyA 4 mg/kg

mPSL pulse, PSL 60 mg/day

IVCY

mPSL pulse, PSL 60 mg/day

MTX 15 mg/w IVIG

PSL 1.5 mg/kg

mPSL pulse

Treatment

Death

Partial improvement

Recovery

Rapidly fatal Recovery

Recovery

This case

[8]

[7]

[6]

[5]

Death

Recovery

[4]

References

Recovery

Outcome

ND not done, N/A not applicable, ESR erythrocyte sedimentation rate, M-CSF macrophage-colony-stimulating factor, TNF-a tumor necrosis factor-alpha, sIL-2R soluble interleukin-2 receptor, IFN-c interferon gamma, sCX3CL1 soluble chemokine (C-X3-C motif) ligand 1, ANA antinuclear antibody, PA-IgG platelet-associated immunoglobulin G. mPSL methylprednisolone, PSL prednisolone, MTX methotrexate , CyA cyclosporin A, IVIG intravenous immunoglobulin, IVCY intravenous cyclophosphamide

Age (years), gender

Patient

Table 1 Hemophagocytic (HPH) syndrome in a patient with dermatomyositis (DM): a case presentation and literature review

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[6] raises the possibility of the first mechanism, as the patient had elevated serum PA-IgG with normal serum complement and circulating immune complexes. The case reported by Kobayashi et al. [7] is consistent with the first and third mechanisms. The patient exhibited increased PA-IgG. Flow cytometric analysis of peripheral blood revealed a significant increase in the B-cell population (CD20) and a slight increase in activated T cells (CD3? and CD25?). Serum showed elevated neopterin, interferon-c (IFN-c), and sIL-2R. This case suggested that platelet-specific antibody facilitated phagocytosis of platelets only, due to activated macrophages in the bone marrow, as suggested by Kumakura et al. [2, 13]. Cooper et al. [14] reported a case of typical immune thrombocytopenic purpura (ITP) complicated by DM. The increased peripheral B cells and elevated serum IgG indicated that B cells were activated in this case. In addition, elevation of CD25? T cells and sIL-2R and IFN-c suggested T-cell activation. These findings are consistent with previous studies demonstrating the pathological roles of both humoral and cell-mediated immunity in DM [15]. Furthermore, IFN-c is a potential activator of macrophages and enhances FcgR expression [16]. Yanjima et al. [8] found that the clinical features of DM differ when complicated by HPS in that systemic symptoms are more severe and thus more intensive therapy is required, suggesting an immune-complex-mediated mechanism with cytokine storms. In their study, IC-C1q was significantly higher in DM patients with than those without HPS. These DM patients with HPS also showed elevated M-CSF and sIL-2R, suggesting activation of macrophages and T cells, respectively. , In previous reports on DM complicated by HLH, steroid therapy such as pulse therapy, immunosuppressants including CyA and intravenous cyclophosphamide (IVCY), and intravenous immunoglobulin (IVIG) was instigated. Despite aggressive steroid therapy, our patient was unable to be saved. Other treatments for HLH accompanying connective tissue diseases, such as plasma exchange therapy (PE) and anticytokine therapies including biologics have been used mainly in adult-onset Still’s disease (AOSD) or systemic juvenile idiopathic arthritis (sJIA) [17–19] but not in DM cases complicated by HLH. Nishida et al. [18] reported the case of a patient with AOSD complicated by hemophagocytic syndrome who lost consciousness due to meningoencephalitis and was successfully treated with PE. They stated that CNS symptoms such as coma and confusion were induced by increased blood cytokines, including IFN-c and sIL-2R, and that PE was effective because it rapidly decreased the circulating cytokine levels. In AOSD or sJIA, TNF-a blockade and anakinra have also been recommended for the treatment of secondary HLH [20, 21]. If a cytokine-mediated mechanism was involved in our patient, the possibility that the patient

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may have responded to PE or biologics cannot be denied. In the early stage of DM, the small blood vessels in muscle tissues are damaged, and CD4? T lymphocytes infiltrate around them. This suggests activation of humoral and cellmediated immunity targeting these vessels [22]. In our patient, infiltration of macrophages was observed, primarily in the liver and spleen. Thus, the following mechanism may have contributed to the onset of HPS: immunocompetent cells activated by DM secreted inflammatory cytokines (especially IFN-c), which caused macrophages to release cytokines (IL-1 and TNF-a) [5]. Although neurological abnormalities have been documented, mainly in familial hemophagocytic lymphohistiocytosis (FHL) in childhood [23], few have been described in adults, especially in AAHS [11]. Previous studies have documented that 30–70 % of HPS patients (mainly FHL) show neurological abnormalities, such as seizures, conscious disorders, hemiparesis, nuchal rigidity, and ataxia. Our patient also had a hemorrhagic necrotic lesion associated with infiltration of macrophages in the brainstem, which may be uniformly consistent with CNS lesions due to HLH [10]. Henter et al. classified the autopsy finding of the CNS lesions in HLH into four stages: stage 0, without neuropathological abnormalities, to stage III, with pronounced diffuse infiltration of lymphocytes and histiocytes/ macrophages in the parenchyma and multifocal tissue necrosis with prominent astrogliosis. Our case seemed to correspond to stage III. The etiology of FHL has remained unclear since Farquhar and Claireaux [24] reported familial hemophagocytic reticulosis. However, perforin was identified as a cause of FHL2 in 1999, and thereafter, four subtypes (FHL2–FHL5) were identified. These disorders commonly involve cytotoxic granules of lymphocytes [25]. All subtypes are initially asymptomatic, but HPS/HLH can be identified phenotypically. Onset is within 1 year of age in 70–80 % of patients with FHL, and nearly all experience onset by 3 years of age, although adult onset has been reported rarely. Our patient had no familial history of HLH (in her grandparents, parents, or sister). Genetic analysis for FHL was not performed, and thus the possibility of FHL cannot be completely ruled out. However, there have been no reports of FHL that developed with symptoms similar to those of DM, so it is unlikely that the patient had FHL. Bone marrow examination revealed euplasia only, with no apparent hemophagocytosis. Autopsy revealed hemophagocytosis in the spleen only, usually a difficult site to biopsy. In nearly 20 % of HLH cases, documenting hemophagocytosis on the first bone marrow specimen is difficult or impossible [26]. However, the inability to demonstrate hemophagocytosis in the initial specimen should not prevent the institution of treatment, provided other clinical criteria are met.

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Conclusions Even when a pathological examination yields no finding of hemophagocytosis, it is important to comprehensively and rapidly diagnose HLH based on the overall clinical picture. Because DM complicated by HPS/HLH may be associated with abnormal production of cytokines and various systemic autoimmune responses, it may be necessary to immediately administer additional potent immunosuppressive therapy, such as IVCY or CyA in corticosteroid-resistant cases [2, 10]. Conflict of interest

None.

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