Successful use of subcutaneous anakinra in hemophagocytic lymphohistiocytosis precipitated by candidiasis in a patient with systemic lupus erythematosus: A case report and description of a novel therapeutic regimen

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal condition characterized by inappropriate immune system activation leading to a “cytokine storm”, and ultimately resulting in end‐organ damage. Causes include primary defects in genes involved in immune‐mediated cytolytic pathways, or secondary triggers such as infection or malignancy. We describe a case of HLH precipitated by fungal infection which occurred as a consequence of immunosuppression for management of systemic lupus erythematosus (SLE) and necrotizing myopathy. The patient presented with immune‐mediated disease of the muscles and lung which was treated with high‐dose corticosteroids and aggressive immunosuppression. HLH emerged in the context of confirmed candidiasis and features of severe sepsis. The patient responded rapidly to antifungal therapy and high‐dose anakinra, which was administered subcutaneously and progressively weaned over 4 weeks. She completed HLH treatment as an outpatient and remains well at 12 months with controlled SLE and no recurrence of HLH.

We present a case of HLH secondary to fungal infection with Candida albicans in a patient with systemic lupus erythematosus (SLE), necrotizing myopathy and rapidly progressive immune-mediated interstitial lung disease (ILD).HLH secondary to esophageal candidiasis has not previously been reported, thus this case is informative in increasing awareness of this clinical possibility.Furthermore, we outline a simple dosing regimen for anakinra which provided rapid control with high-dose subcutaneous therapy which was weaned over 28 days and completed as an outpatient.This regimen was efficacious and well-tolerated and represents a novel therapeutic approach.

| C A S E REP ORT
A 43-year-old woman presented with fever on a background of SLE diagnosed overseas 20 years prior and treated with hydroxychloroquine.Examination revealed nailbed splinter hemorrhages, and transesophageal echocardiogram demonstrated an echo-dense mass on the tricuspid valve.Cultures and serological tests for atypical pathogens were negative and Libman-Sacks endocarditis was considered likely.Symptoms improved following an increase in hydroxychloroquine dose to 400 mg daily.She was noted to be negative for antinuclear antibodies (screening titer 1/80); however, anti-double-stranded DNA antibodies were positive (28 IU/mL, reference range (RR) 0-10 IU/mL) and C3, C4 complement levels were low (0.69 g/L, RR 0.9-1.8g/L, and 0.09 g/L, RR 0.1-0.4g/L respectively).
One week later, she developed proximal muscle weakness with no cutaneous or respiratory features.Creatinine kinase (CK) was elevated at 1000 U/L (RR 30-150 U/L) suggestive of myositis although myositis auto-antibodies were negative.Vastus lateralis muscle biopsy confirmed necrotizing myopathy with human leukocyte antigen-1 upregulation consistent with immune-mediated pathology; acid phosphatase staining also raised the possibility of hydroxychloroquine toxicity.The latter was ceased and she commenced oral prednisone 1 mg/kg.Computed tomography pulmonary angiogram performed due to progressive dyspnea revealed pulmonary embolism together with nonspecific interstitial pneumonia (NSIP)-pattern ILD.Anti-phospholipid antibodies were negative as were repeat microbiological investigations.An intracardiac shunt was not detected, and valvular embolism considered possible.Therapeutic anticoagulation was commenced, together with intravenous (IV) methylprednisone 1000 mg for 3 days and IV cyclophosphamide for treatment of SLE-associated myositis with ILD.
CK levels improved, and she was discharged on prednisone and warfarin with planned ongoing IV cyclophosphamide, but represented within 5 days with worsening breathlessness and hypoxemia.IV ceftriaxone and doxycycline were added due to bilateral lower lobe consolidation on CT; however, cultures and directed testing for atypical pathogens were persistently negative.Due to ongoing fevers, antimicrobial therapy was broadened.
Her condition worsened, necessitating further methylprednisone, IV immunoglobulin (IVIG) 2 g/kg, and rituximab induction for progressive immune-mediated lung disease.She developed a sore throat and oral mucosal lesions, and commenced nystatin due to isolation of candida from her throat.Anakinra was chosen to minimize the risk of worsening sepsis in a critically ill patient.She commenced dexamethasone, together with subcutaneous anakinra 100 mg 8-hourly.Anakinra was weaned after 2 weeks to 100 mg twice daily for 1 week, followed by daily dosing to complete a total of 28 days therapy.Clinical improvement was rapid, with resolution of fevers and progressive reduction in ferritin.Corticosteroid dose was progressively reduced, to a maintenance dose of 5 mg/d prednisone.IVIG was administered every 4 weeks for maintenance immunomodulation, and cyclosporine was added for control of SLE.The patient remains clinically well at 12 months.

| DISCUSS ION
This case describes the occurrence of HLH in a patient with fungal infection and rheumatologic disease, with both factors possibly contributory.Features of HLH evolved while the patient was receiving significant immunosuppression for SLE management and coincided with the detection of candida infection, thus this was considered a likely precipitant.Fungal infections such as candidiasis precipitating HLH are sparsely reported; previous reports include descriptions of simultaneous disseminated candida and Epstein-Barr virus infection 5 and disseminated histoplasmosis, usually in the setting of human immunodeficiency virus or immunosuppression. 6We therefore describe a unique case of esophageal candidiasis associated with HLH, with no evidence of fungemia or bone marrow infiltration.Our case also highlights the importance of considering HLH in the setting of acute clinical deterioration and sepsis.
HLH complicating rheumatologic disease is termed MAS, classically seen in systemic juvenile idiopathic arthritis (sJIA), or Still's disease in adults. 3SLE is a known trigger of MAS in adult patients, usually in the context of disease flare or concurrent infection, as occurred in our patient. 7There is increasing awareness of MAS occurring in the setting of myositis, with a recent case series reporting an association between MAS development and myositis severity as well as acute exacerbations of ILD. 8 This association is evident in our patient's clinical course, and an intriguing correlation between ferritin and CK levels was observed, with levels of each rising and falling together.This observation may reflect an intrinsic link between myositis and HLH/MAS disease activity and/or a common pathophysiology underlying both conditions, and reflects that treatment of one disease leads to improvement in the other.Notably, early diagnosis of HLH can be challenging due to the reduced sensitivity of the HLH-2004 diagnostic criteria in the setting of severe rheumatologic disease. 3 HLH secondary to an identifiable trigger, treatment of the underlying cause is recommended. 9Our treatment regimen aimed to rapidly attenuate the hyper-inflammatory state of HLH without exacerbating underlying infection and immune-mediated disease.
We employed high-dose corticosteroids, fluconazole and anakinra, a monoclonal anti-interleukin-1 antibody which has demonstrated success in the treatment of HLH in children.Anakinra in HLH abrogates the cytokine storm; a recent case series of 16 adults with secondary HLH demonstrated survival benefit, most marked in HLH triggered by rheumatologic disease. 10Phase III trials have shown an excellent safety profile in the setting of sepsis (in contrast to etoposide), a relevant comorbidity in this patient. 11Numerous anakinra dosing strategies have been reported, including IV anakinra infusion for critically unwell patients. 12Our approach featured a convenient tapering regimen whereby anakinra was initiated at high dose for rapid disease control (100 mg 8-hourly) subcutaneously for 2 weeks, followed by 100 mg twice daily for 1 week, then 100 mg daily dosing for 1 week, for a total of 28 days of treatment.This strategy produced a rapid and sustained clinical and biochemical response, without recurrence of HLH.
In conclusion, we present a rare case of HLH triggered by invasive fungal infection in the context of immunosuppression for SLE and immune-mediated myositis and lung disease.The use of high-dose subcutaneous anakinra in a convenient, tapering regimen afforded rapid and sustained disease control without exacerbation of sepsis in a high-risk and complex patient.To our knowledge, this is the first report outlining the utility of a novel 4-week weaning regimen of high-dose subcutaneous anakinra in the management of HLH precipitated by fungal infection in a patient with SLE.
The patient developed hypotension, and required vasopressors and intensive care admission.Imaging demonstrated new esophageal thickening consistent with systemic candidiasis and IV fluconazole was added.Ferritin, which had been normal 2 weeks prior, was significantly elevated on repeat testing at 54354 μg/L (RR 30-150 μg/L).Natural killer (NK) cell function testing showed reduced degranulation.Bilineage cytopenia emerged, with a nadir hemoglobin of 64 g/L (RR 120-150 g/L) and platelets 98 × 10 9 /L (RR 150-400 × 10^9/L), and bone marrow examination revealed prominent histiocyte hemophagocytosis.She therefore fulfilled at least 5 of 8 criteria for a diagnosis of HLH as defined by HLH-2004 guidelines.Her condition necessitated urgent treatment for life-threatening HLH precipitated by invasive candidal infection in the context of extensive immunosuppression and rheumatological disease.