New-onset systemic lupus erythematosus presenting with macrophage activation syndrome: A case report of rare and life-threatening complication

INTRODUCTION

Systemic lupus erythematosus (SLE) is an autoimmune, multisystem, inflammatory disease¹ that occurs as a result of intolerance towards nuclear self-antigens and formation of pathogenic autoantibodies.² Hematologic complications³ in the form of autoimmune hemolytic anemia, antiphospholipid syndrome, and secondary immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), have often been reported in SLE patients. Macrophage activation syndrome (MAS) is one such rare hematological complication that has seldom been reported.

MAS is a type of hemophagocytic lympho-histiocytosis (HLH), accounting for 7.0-15.3% of secondary HLH.^4,5 It is encountered in autoimmune disorders.⁶ MAS is sometimes the presenting manifestation of rheumatological conditions such as SLE, which poses a challenge to the diagnosis of both these conditions. We hereby report one such case of MAS, which surfaced as the first presentation of SLE and was effectively managed with high-dose methylprednisolone, oral prednisolone, and intra-venous immunoglobulins (IVIGs).

CASE REPORT

A young woman, 2 months postpartum, presented to the hospital with progressively worsening lethargy, anorexia, and malaise after a tubal ligation. She also reported significant weakness in both her lower limbs for 20 days, which eventually progressed to involve both her upper limbs over the following 10 days. She had a single febrile episode 3 days prior to admission. The patient was immunocompetent with no recent infections. She denied a history of miscarriages or preterm deliveries and had no history suggestive of prior thromboses. There was no significant history of rheumatic or autoimmune diseases among family members. On arrival, she was critical with hypotension of 90/60 mmHg. Neurological examination revealed generalized hypotonia with severe weakness in all four limbs (power 2/5).

Initial Investigations [Table 1] revealed notable hematological abnormalities like anemia and thrombocytopenia, deranged liver function parameters suggestive of a cholestatic pattern with hypoalbuminemia, deranged renal parameters, with significant proteinuria and dyselectrolytemia.

Her condition necessitated immediate intensive care unit (ICU) admission, where she was started on ionotropic support and IV fluid therapy. Initial assessment was suggestive of an infectious (dengue, malaria, leptospirosis, brucellosis, tuberculosis, human immunodeficiency virus (HIV)) or inflammatory-autoimmune (vasculitis, sarcoidosis, SLE) etiology, with multisystem involvement. A preliminary diagnosis of sepsis (bacterial/viral/fungal) was entertained, and the patient was screened for the source of infection. In view of the same, she was initiated on empirical intravenous antibiotics and supportive care. However, when blood cultures revealed pan-resistant Klebsiella pneumoniae, targeted antimicrobial therapy was commenced.

Nerve conduction study (NCS) was done as part of neurological assessment, which revealed sensory axonal neuropathy and common peroneal sensorimotor neuropathy, consistent with a postinfectious or inflammatory etiology. Meanwhile, her anemia and thrombocytopenia worsened, necessitating multiple transfusions of packed red blood cells, random donor platelets, and fresh frozen plasma. Infectious disease workup comprising malarial antigen, dengue, Leptospira, and Brucella serology yielded negative results. Mantoux and HIV serology tests were also negative. However, a positive direct coombs test confirmed autoimmune hemolysis. Based on clinical findings and the abovementioned serological results, we proceeded with an anti nuclear antibody by indirect immunofluorescence (ANA IF) test, which was positive (intensity 2+). Subsequently, ANA profile was strongly positive for nucleosome and ribosomal-P antibodies, with markedly reduced complement levels (C3 levels - 48 mg/dL). This prompted a detailed assessment for SLE. The diagnosis of SLE was made according to the Systemic Lupus International Collaborating Clinics classification criteria and the 2019 europeon alliance of associations for rheumatology (EULAR)/american college of rheumatology (ACR) Classification criteria for SLE.

Further investigations revealed elevated inflammatory markers, including triglycerides at 303 mg/dL, ferritin at 750 ng/mL, and fibrinogen at 236 mg/dL. These findings, in conjunction with her systemic symptoms, satisfied the 2016 classification criteria for MAS [Table 2], solidifying the diagnosis of MAS as a hyperinflammatory complication of her recent diagnosis of SLE.

Systemic involvement was extensive, with imaging studies demonstrating polyserositis, bilateral pleural effusion, minimal ascites, and hepatomegaly with fatty liver. A 24-hour urine protein collection revealed significant proteinuria, raising concerns of evolving lupus nephritis. Cardiac evaluation uncovered mild left ventricular systolic dysfunction with an ejection fraction of 45%, global hypokinesia, and elevated pulmonary artery pressure (PASP: 40 mmHg), indicative of lupus myocarditis.

Management required a multifaceted approach. Our patient responded well to high-dose intravenous methylprednisolone (500 mg/day for 5 days consecutively) as part of the initial immunosuppressive therapy, followed by oral prednisolone (10 mg) thrice daily for a week, followed by twice daily for 2 weeks. IVIG was introduced to mitigate the hyperinflammatory state. She also commenced on mycophenolate mofetil (MMF-S) (350 mg) twice daily for 2 weeks and hydroxychloroquine (HCQ) (200 mg) twice daily for long-term disease control. Supportive measures included nutritional support through a nasogastric tube due to vocal cord edema and ongoing transfusions to manage her hematological abnormalities.

She was successfully extubated and transitioned to non-invasive ventilation. Neurologically, her strength improved such that spontaneous lower limb movements were noted during ICU stay, and subsequently, the patient was able to mobilize bedside. She showed significant improvement over the period of admission, which lasted for 2 weeks, with the stabilization of her hematological parameters and resolution of fever. At the time of discharge, the patient was hemodynamically stable and was continued on oral prednisolone, MMF-S, HCQ, and a structured follow-up plan.

DISCUSSION

HLH disease is a hyperinflammatory and dysregulated immune state, which can be primary or secondary. Familial or genetic HLH may be a consequence of defects in perforin-dependent cytotoxicity or mutations in genes UNC13D and STX11 on chromosomes 17q25 and 6q24, respectively.⁷ Meanwhile, secondary HLH is triggered by infections (viral, bacterial, or fungal) or can occur in the setting of rheumatologic conditions such as systemic juvenile idiopathic arthritis (JIA), SLE, Still’s disease, or systemic onset juvenile rheumatoid arthritis.⁸

MAS refers to a form of HLH that occurs primarily in patients with systemic JIA or other rheumatological conditions. The classification criteria of MAS were well described in 2016 by EULAR/ACR.⁹ The occurrence of MAS in SLE has been reported to range from 0.9% to 4.6%.¹⁰ Due to a similarity in their presentation, diagnosing MAS in the backdrop of SLE can be challenging. This contributes to the high morbidity and mortality associated with a late diagnosis of MAS. MAS contributes to significant mortality among adult patients if left unrecognized or without appropriate treatment.¹¹

According to existing medical literature, the most common clinical presentations of MAS are fever, splenomegaly and/or hepatomegaly, raised lactate dehydrogenase levels, hematological abnormalities like anemia, thrombocytopenia, and/or leucopenia with occasional involvement of central nervous system (CNS).^12,13 Likewise, our patient also manifested with fever, profound lethargy, anorexia, and malaise, alongside hepatomegaly and CNS involvement in the form of generalized hypotonia with severe weakness in all four limbs (power 2/5). Her hematological profile was also compatible with MAS.

In comparison to the general population, SLE patients are more susceptible to MAS because of immune dysregulation.¹⁴ Additionally, SLE presenting for the first time with MAS is rare.^15,16 Febrile SLE patients presenting with anemia/leucopenia or thrombocytopenia, hepatic dysfunction, and raised ferritin levels should raise the suspicion of MAS^17,18 and should be adequately worked up for the same. Interestingly, neurological manifestations were found more commonly in SLE patients with MAS than those without,¹³ which was evident in our patient. Clinical neurological involvement was present, as assessed by symptomatology, examination, and further assessment, through an NCS, which revealed sensory axonal neuropathy and common peroneal sensorimotor neuropathy.

To the best of our knowledge, there are only 26 cases reported in English medical literature where MAS was diagnosed at the onset of SLE.^19-22 However, there are several other reports of MAS in relation to flare-ups or complications of SLE.^19,23. Due to overlapping clinical features such as fever, organomegaly, lymphadenopathy, and cytopenia, flare-up of underlying autoimmune diseases like SLE can be wrongly labelled as MAS. This close mimicry in clinical presentation can hinder the timely recognition of MAS and thereby delay the selection of the most appropriate therapeutic approach.²⁴

The diagnosis of early MAS is usually difficult due to the absence of a characteristic clinical or laboratory feature. A febrile patient is diagnosed with MAS if it is accompanied by elevated serum ferritin levels, alongside thrombocytopenia, hypofibrinogenemia, elevated aspartate aminotransferase (AST), and triglyceride levels.⁹ However, establishing a diagnosis of MAS in our patient was not straightforward since a likely infection interposed active SLE. Unfortunately, MAS in SLE does not have a validated diagnostic criterion, which is likely a grey area. Hence, it becomes pertinent to keep a febrile SLE patient under monitoring for the 2016 MAS classification criteria, which could contribute to its early identification.²⁵ However, raised ferritin level is reputed to be the most specific and sensitive marker for distinguishing between MAS-associated SLE from active SLE.⁷

The recommended first-line treatment for MAS consists of high-dose corticosteroids such as methylprednisolone.²⁶ Our patient responded well to high-dose intravenous methylprednisolone (500 mg/day for 5 days consecutively) as part of the initial immunosuppressive therapy, followed by oral prednisolone (10 mg) thrice daily for a week, followed by twice daily for 2 weeks. IVIG was introduced to mitigate the hyperinflammatory state. She was also commenced on MMF-S (350 mg) twice daily for 2 weeks and HCQ (200 mg) twice daily for long-term disease control.

The prognosis of MAS is variable, with factors such as underlying cause, age of the patient, and co-existing complications determining its long-term outcome. Overall, the outcome of MAS is favorable in cases of timely diagnosis and effective management. Most patients recover with minimal long-term effects, while occasionally recurrence has been documented despite adequate treatment.

CONCLUSION

This case underscores the complexity of early recognition of a life-threatening complication such as MAS during the first presentation of SLE, particularly in a postpartum setting. It is pertinent to maintain a high index of suspicion for the same, as early detection improves prognosis. It is also of clinical value to distinguish MAS from a flare-up of SLE, as there exists an overlap between the two. Our patient was promptly treated for this SLE-associated MAS with a multidisciplinary approach, which was instrumental in achieving a favorable outcome.