Macrophage activation syndrome as an initial presentation of systemic lupus erythematosus with sensorineural hearing loss in a young male patient

Abstract

An 18-year-old male adolescent presented with prolonged high spiking temperature, photosensitive rash, oral ulcers and reduced hearing bilaterally of recent onset. Examination revealed malar rash, vasculitis rash over bilateral palms and soles, oral and buccal ulcers, palpable posterior auricular and inguinal lymph nodes, and reduced hearing bilaterally. His further investigations noted pancytopaenia, elevated transaminases, hyperferritinaemia, low C3 and C4 levels, positive antinuclear antibody, double-stranded DNA and direct Coombs test, while bone marrow aspiration revealed active phagocytic activity suggestive of hemophagocytic syndrome. We made a diagnosis of systemic lupus erythematosus with macrophage activation syndrome. We treated him with pulse intravenous methylprednisolone and his condition improved drastically. Temperature resolved on the next day after intravenous methylprednisolone; bilateral sensorineural hearing loss improved to near-normal hearing after treatment. He remained well during follow-up with a tapering dose of prednisolone.

Background

Haemophagocytic lymphohistiocytosis (HLH) is an aberrant hyperinflammatory, hyperferritinemic immune response syndrome driven by macrophages and cytotoxic T cells.¹ This condition is associated with a potential fatal cytokine storm. Secondary HLH due to autoimmune disease is known as macrophage activation syndrome (MAS).² Patients often suffer from recurrent fever, cytopaenia, liver dysfunction and a sepsis-like syndrome that may rapidly progress to terminal multiple organ failure. It is rare as the first manifestation of systemic lupus erythematosus (SLE). We report an unusual case of new-onset SLE presented with MAS and sensorineural hearing loss.

Case presentation

An 18-year-old Malay male adolescent with a background medical history of glucose-6-phosphate dehydrogenase (G6PD) deficiency presented with prolonged high spiking fever associated with oral ulcer, malar rash, photosensitivity and reduced hearing bilaterally of recent onset. His appetite had reduced, and he had lost 3 kg of body weight in 2 weeks’ duration. Otherwise, he denied joint pain, sicca symptoms, abdominal pain and high-risk behaviour; he neither smoked nor consumed alcohol. He denied taking traditional or over-the-counter medicines. Physical examination revealed malar rash, vasculitis rash over bilateral palms and soles, oral and buccal ulcers, and reduced hearing bilaterally. There were palpable lymph nodes over the right posterior auricular region (5×3 cm) and left inguinal region (5×5 cm). There was no muscle tenderness/weakness; neurological, respiratory and cardiovascular examinations were unremarkable.

Investigations

Further investigation revealed pancytopaenia (white blood count 0.98×10³/μL (normal range (NR): 4–11×10³/μL), absolute neutrophil count 0.36×10³/μL (NR: 2–7×10³/μL), haemoglobin 6.3 g/dL (NR: 13–17 g/dL) (hypochromic microcytic), platelet 90×10³/μL (NR: 150–450×10³/μL), raised transaminases (alanine aminotransferase 111 U/L (NR: 10–49 U/L), aspartate aminotransferase 153 U/L (NR: 9–48 U/L)), positive direct Coombs test, C3 level 0.34 g/L (NR: 0.85–1.60 g/L), C4 level 0.08 g/L (NR: 0.12–0.36 g/L), ferritin level of 9709 ng/mL (NR: 22–322 ng/mL), fibrinogen 278 mg/ dL (NR: 150–450 mg/dL), C reactive protein 5.08 mg/L (NR: 0–5 mg/L) and triglyceride 239.2 mg/dL (NR: <150 mg/ dL). Antinuclear antibody (ANA) by immunofluorescence method was positive (1:320) with a homogeneous pattern, double-stranded DNA (dsDNA)-positive, extractable nuclear antigen revealed positivity for anti-Sm, anti-RNP, and anti-Ro antibodies. Initial urinalysis demonstrated 0.3 g/L of protein and 1.0 mg/L of blood; however, urine protein and blood were completely resolved within 1 week of treatment. Hence, further investigation for lupus nephritis was not pursued. Serial blood cultures were negative; viral screening for hepatitis B, hepatitis C, HIV, cytomegalovirus and Epstein-Barr virus were all non-reactive. Pure tone audiometry revealed bilateral mild sensorineural hearing loss (figure 1). Ultrasound abdomen showed mild splenomegaly (13 cm) and minimal ascites. Excision biopsy of the left inguinal lymph node demonstrated reactive lymphoid hyperplasia with no evidence of hemophagocytosis or malignancy. Bone marrow aspiration showed an increase in macrophages, with active phagocytic activity suggestive of hemophagocytic syndrome (figure 2).

Figure 1.

Pure tone audiometry before (A) and after (B) treatment. Red circle for the right ear, blue cross for the left ear. ANSI, American National Standards Institute; dB HL, decibel hearing level; HL, hearing level.

Figure 2.

May-Grunwald-Giemsa staining of bone marrow aspirate observed under light microscopy 20×10 magnifications (A) and 40×10 magnifications (B, C). Red arrows show neutrophils ingested by the histiocytes, demonstrating macrophages with active phagocytic activity.

Differential diagnosis

He was initially treated for an infection with an unknown source in a district hospital, but his symptoms persisted. He was referred to our centre for further management. What struck us during the presentation were the high spiking temperature (up to 40⁰C), features of SLE, pancytopaenia and elevated transaminases. Differential diagnoses included SLE with cytopaenias, MAS, infection or lymphoproliferative disease. We excluded infection by negative serial blood cultures and viral screening. We also excluded drug-induced cytopaenias by obtaining a detailed past medication history. Lymphoproliferative diseases were ruled out as peripheral blood film, bone marrow aspiration and lymph node histopathology did not show evidence of haematological malignancy.

He fulfilled the classification criteria of SLE based on 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendation.³ He had a high titre of ANA, fever (2), leucopenia and thrombocytopaenia (4), acute cutaneous lupus (6), low C3 and C4 levels (4), and positive anti-dsDNA/anti-Sm (6) (total of more than 10 points). He also fulfilled the 2016 EULAR/ACR classification criteria for MAS.⁴ He had raised ferritin level, aspartate aminotransferase and triglyceride, but low platelet and fibrinogen. Therefore, our patient’s condition was consistent with MAS in a newly diagnosed SLE.

Treatment

He was treated with pulse intravenous methylprednisolone (total 3 g given). His temperature settled on the next day, and his skin lesion, pancytopaenia and transaminitis improved. He remained well and was discharged with oral prednisolone 50 mg daily (1 mg/kg/day). The prednisolone dose was tapered by 10 mg every month until a dose of 20 mg daily. Subsequently, the dose was reduced by 2.5 mg each month. He remained well on oral prednisolone 12.5 mg daily. Hydroxychloroquine was initiated during the outpatient review; no haemolysis of red blood cells was observed.

Outcome and follow-up

During the follow-up of the past 7 months, he complied to prednisolone and hydroxychloroquine. No additional immunosuppressant was added. He remained well, afebrile with no sign of active SLE. His blood parameters (blood counts, ferritin and liver enzymes) normalised. Repeated pure tone audiometry 1 month post-treatment showed near-normal hearing on the left side and improved hearing on the right side with mild residual hearing impairment (figure 1).

Discussion

HLH is underdiagnosed, and its actual incidence is unknown. HLH further classified into primary and secondary causes, depending on the aetiology. The primary cause of HLH, or familial, is related to mutations in the gene encoding perforin (PRF), UNC13D (17q25) and STX11 on chromosome 6q24.⁵ Meanwhile, secondary HLH can be due to malignancy (mainly haematological malignancy, such as lymphoma), infection (virus/bacteria or fungal) or autoimmune diseases (SLE/juvenile idiopathic arthritis).⁶ Secondary HLH due to autoimmune disease is known as MAS.

MAS is one of the secondary HLHs caused by autoimmune disease. Classification criteria of MAS were well described in 2016 by EULAR/ACR.⁴ MAS due to SLE was estimated to be 0.9%–4.6%.⁷ The most common clinical presentations were fever (87%–100%), splenomegaly (36.4%), hepatomegaly (18.2%), central nervous involvement (30%), leucopenia (87%), anaemia (83%), thrombocytopaenia (87%), and raised aspartate aminotransferase or lactate dehydrogenase (60%).^{7 8} Previous reports demonstrated that serum ferritin level ranged 927–14 760 ng/mL, and aspartate aminotransferase ranged 54–815 μ/L.⁶ Compared with our patient, he had a persistent high fever, pancytopaenia, mild splenomegaly and minimal ascites, but no liver enlargement. Splenomegaly and ascites could be due to MAS or SLE. No biopsy was done to the spleen as the size was just mildly enlarged. We did not perform abdominocentesis because the ascites was minimal. His blood parameters were also compatible with MAS. Mortality in MAS is high. Fukaya et al reported the mortality of MAS to be as high as 20%. The prognosis will be poor with the presence of an infection and C reactive protein of more than 50 mg/L.⁷ Fortunately, our patient did not have any of the poor prognostic factors. Early diagnosis of MAS and prompt treatment provide the most favourable outcome. However, for our patient, making a diagnosis of MAS may not be straightforward as his condition mimicked infection, malignancy and active SLE. Often, the condition may coexist, therefore rendering further diagnostic challenges.

Among the secondary causes of HLH, it is crucial to differentiate autoimmune-related from other causes such as infection or malignancy because the treatment differs significantly. For MAS, the recommended first-line treatment consists of high-dose corticosteroids (methylprednisolone 1 g/day 3–5 days consecutively).² Other agents such as ciclosporin, anakinra (interleukin (IL)-1 receptor antagonist) and tocilizumab (IL-6 monoclonal antibody) may be added in patients with inadequate response to first-line therapy. In the cases of central nervous system involvement, etoposide (50–100 mg/m²) once per week may be effective,¹ whereas other secondary HLHs need specific treatment, such as chemotherapy for malignancy and antiviral/antibiotics/antifungal for infective causes. Our patient was given hydroxychloroquine as part of the SLE treatment. Even though he has G6PD deficiency, he did not develop haemolytic anaemia throughout the course of treatment. Our observation was consistent with a recent study which supported the use of hydroxychloroquine even if the presence of G6PD deficiency.⁹

Our patient reported a new onset of bilateral hearing loss, confirmed by pure tone audiometry. In a meta-analysis, the prevalence of sensorineural hearing loss was discovered in 6%–70% of SLE patient. An autoimmune response, immune complex deposition and cytotoxic damage contributed to the damage of inner ear.¹⁰ Sensorineural hearing loss has been observed in haemophagocytic syndrome; however, the exact mechanism is not clearly understood. Imashuku et al reported a case of sensorineural hearing loss in familial HLH, but this was detected after the treatment of stem cell transplantation.¹¹ Tamura et al reported sensorineural hearing loss in a case of secondary HLH with infection.¹² Both authors believed that high cytokine levels might be the culprit of inner ear dysfunction. Even though we were not able to identify the exact aetiology of sensorineural hearing loss in our patient (MAS vs SLE), he responded very well with treatment. Hearing symptoms should be explored in all patients with MAS in order to confirm the exact pathophysiology in the future.

Learning points.

• First presentation as MAS in SLE is rare.

• The diagnosis of MAS requires a high index of suspicion, the better prognosis with earlier detection and treatment.

• It is crucial to differentiate the secondary causes of HLH as the treatment differs significantly.