Case of using mycophenolate in combination with steroids for concurrent macrophage activation syndrome and lupus flare

Abstract

This report highlights the importance of tailored treatment strategies in severe systemic lupus erythematosus (SLE) flares driving the life-threatening condition, macrophage activation syndrome (MAS). We report the case of a 42-year-old woman with active systemic lupus erythematosus (SLE) who was diagnosed with MAS within 3 days of onset of lethargy, rash, joint pain and significant cytopenias. This early diagnosis meant that her condition was managed with less intensive immunosuppression with only modest doses of steroids and mycophenolate mofetil.

Background

Macrophage activation syndrome (MAS) is a rare but life-threatening condition characterised by dysfunctional macrophage activation leading to overproduction of cytokines and phagocytosis of erythrocytes, leucocytes and platelets.¹ Due to its mimicry of other conditions, it is often under-recognised leading to significant delays in diagnosis.

We describe a case of a young woman with active systemic lupus erythematosus (SLE) manifested as lethargy, rash and joint pain and within 3 days of onset of significant cytopenias was diagnosed with MAS. This early diagnosis meant that her condition responded and resolved with less intensive immunosuppression.

This case demonstrates the need to consider the underlying pathophysiology and severity of MAS in SLE in order to tailor the treatment strategy for the individual patient.

Case presentation

We describe the case of a woman who originally presented aged 26 years with fevers, fatigue and cervical lymphadenopathy. A lymph node biopsy demonstrated a necrotising lymphadenitis consistent with Kikuchi’s disease. She received symptomatic treatment and her symptoms resolved.

When aged 37, she had developed lymphadenopathy, fever, malaise as well as a scaly erythematous rash initially affecting her cheeks but then spreading to involve her chest and upper arms. In addition, she was experiencing generalised joint pains, morning stiffness, a low-grade fever and alopecia. A diagnosis of SLE was made and treatment was commenced as per below.

At the age of 42 years, she became more unwell with recurrence of the rash, lethargy, back pain, nausea and parotid pain.

Investigations

Initial investigations demonstrated a raised erythrocyte sedimentation rate, positive antinuclear antibodies (1:160) and anti-dsDNA antibodies (149 IU/mL), positive anti-Ro, anti-ribonucleoprotein and anti-SM antibodies based on which she was diagnosed with SLE.

In early 2018, blood tests showed pancytopenia (white cell count: 3.1, platelets: 131, haemoglobin: 87), with a raised lactate dehydrogenase (LDH) (592 U/L), ferritin 3300 ug/L and triglycerides 3.81 mmol/L. There was a concurrent rise in anti-dsDNA antibodies and a fall in complement levels. CT scan of chest, abdomen and pelvis revealed no lymphadenopathy. A bone marrow trephine biopsy demonstrated atypical/dysplastic features and haemophagocytosis.

Differential diagnosis

With the development of MAS in the context of SLE, broad differential diagnosis was explored.

This included infection, including tuberculosis, Epstein-Barr virus, HIV, were considered. Underlying malignancy, in particular, haematological malignancies such as lymphoma were important to investigate for and finally severe active lupus itself.

Further developments in the case are discussed in the ‘treatment’ section where pertinent investigations point to the diagnosis.

Treatment

Following the initial diagnosis of SLE, she was commenced on treatment with a reducing dose regimen of prednisolone as well as hydroxychloroquine 200 mg two times per day with significant improvement in her symptoms. On reducing the prednisolone dose, she found her symptoms worsened, particularly with regards to joint pains and rash. She was, therefore, commenced on treatment with azathioprine 50 mg daily and remained well. She was keen to reduce the amount of medication she was taking so stopped azathioprine.

She was unwell towards the end of December 2017, resulting in hospital admission in January 2018 with right-sided neck and jaw pain along with swelling over the parotid region. Ultrasound examination findings revealed bilateral parotitis. She was treated with clindamycin for suspected infective parotitis and her symptoms resolved. A week later, she developed an erythematous scaly rash, initially affecting her face but then spread to cover her whole body. Histological findings of the skin biopsy were suggestive of a drug rash. However, laboratory parameters revealed elevated anti-dsDNA antibodies (276 IU/mL) and low complement (C3: 0.47 g/L, C4: 0.08 g/L). These findings were indicative of a flare-up of SLE leading to MAS and she was treated with a single dose of intravenous methylprednisolone 1 g and commenced on mycophenolate mofetil 1 g two times per day with reducing dose regimen of oral prednisolone 40 mg daily.

Outcome and follow-up

She was monitored frequently for signs of flare-up of lupus and to evaluate for MAS. Laboratory parameters were also measured daily for a week and subsequently, weekly.

There was a significant improvement in her symptoms consistently. Over 5 weeks, the laboratory markers including ferritin, LDH, white cell count, platelets, triglycerides and haemoglobin normalised (figures 1–6). At 18 months since concurrent diagnosis of MAS and lupus flare, she remains well on a combination of mycophenolate 2.5 g daily and oral prednisolone of 5 mg daily and maintenance hydroxychloroquine 200 mg once daily. Please refer to figure 7 for a timeline of events.

Figure 1.

Improvement in ferritin demonstrated after treatment with mycophenolate mofetil, suggesting an overall resolution of MAS. Red star denotes treatment initiation. MAS, macrophageactivation syndrome.

Figure 2.

Improvement in LDH demonstrated after treatment with mycophenolate mofetil, suggesting an overall resolution of MAS. Red star denotes treatment initiation. LDH, lactatedehydrogenase; MAS, macrophageactivation syndrome.

Figure 3.

Improvement in white cell counts demonstrated after treatment with mycophenolate mofetil, suggesting an overall resolution of MAS. Red star denotes treatment initiation. MAS, macrophageactivation syndrome.

Figure 4.

Improvement in haemoglobin demonstrated after treatment with mycophenolate mofetil, suggesting an overall resolution of MAS. Red star denotes treatment initiation. MAS, macrophageactivation syndrome.

Figure 5.

Improvement in platelet count demonstrated after treatment with mycophenolate mofetil, suggesting an overall resolution of MAS. Red star denotes treatment initiation. MAS, macrophageactivation syndrome.

Figure 6.

Improvement in triglycerides demonstrated after treatment with mycophenolate mofetil, suggesting an overall resolution of MAS. Red star denotes treatment initiation. MAS, macrophageactivation syndrome.

Figure 7.

Timeline of the patient’s journey from the start of her illness. ABS, antibodies; ANA, antinuclear antibodies; BD, two times per day; ESR, erythrocyte sedimentationrate; LDH, lactate dehydrogenase; LN, lymph node; MAS, macrophage activationsyndrome; OD, once daily; RHEUM OPD, rheumatology outpatient department; SLE, systemic lupus erythematosus; US, ultrasound.

Discussion

MAS is a systemic, life-threatening illness which is a secondary haemophagocytic lymphohistiocytosis (HLH) occurring as a complication of autoimmune disease. It is due to excessive stimulation of immune cells, resulting in a cytokine storm (including interleukin (IL)-2, IL-1, IL-6, IL-18, interferon gamma, tumour necrosis factor-alpha, macrophage colony-stimulating factor) and the clinical presentation of fever, hepatosplenomegaly, lymphadenopathy and bleeding abnormalities.² The laboratory abnormalities associated with MAS including hyperferritinaemia, cytopenia and raised triglycerides occur late in the illness and result in delayed diagnosis and high mortality. The true incidence of MAS remains unknown due to its under-recognition. The most common autoimmune disease associated with MAS is systemic juvenile idiopathic arthritis where the estimated prevalence is 10%.³

Up to 4.6% of SLE cases have been complicated by MAS, with an even higher proportion in those with liver disorders.² Almost a quarter of newly diagnosed patients with juvenile SLE displayed features of MAS in a retrospective review, and these patients had more pronounced neurological involvement.⁴ Concurrent MAS and flare-up of lupus have been previously described⁵ and MAS may be the presenting feature of SLE.⁶ However, clinical features and laboratory indices may not clearly distinguish a lupus flare from MAS, which is associated with high mortality. Therefore, a combination of potent immunosuppressants is used to treat concurrent MAS and lupus flare.

In this case, a high index of suspicion of MAS led us to obtain appropriate investigations without delay. Thus, securing an early diagnosis and treatment.

We hypothesised that active lupus manifesting in skin and parotid glands was triggered by T-cell infiltration and seemed to respond favourably to relatively low-dose corticosteroid therapy. Ciclosporin and other immunosuppressive agents such as etoposide, cyclophosphamide, rituximab and plasma exchange have been used effectively to treat MAS in the context of lupus.⁷ Treatment with ciclosporin is associated with a significant adverse effect profile. Therefore, an alternative immunosuppressive regimen with mycophenolate was considered in combination with a low to moderate dose of oral corticosteroids.

We monitored the clinical features and laboratory parameters regularly. We used the trend of changes in laboratory parameters to guide treatment decisions. As previously reported, we found that it may take weeks for the laboratory parameters to normalise, whereas the trend of the kinetics of biochemical parameters was evident at a shorter time interval and is likely influenced by the activation status of macrophages perhaps reflecting their role in lipid metabolism. Over 5 weeks from the first dose of intravenous methylprednisolone and mycophenolate, we noted significant improvement in clinical symptoms, signs and normalisation of laboratory parameters, sustained at a 6-month follow-up.

To our knowledge, there exists only one previous case report where mycophenolate alone in combination with a relatively modest dose of corticosteroids has been used to treat MAS in a patient with multisystem lupus manifested by glomerulonephritis, pericarditis and retinal vasculitis.⁸ On presentation, he fit the HLH diagnostic criteria (fever, hepatosplenomegaly, pancytopenia, hyperferritinaemia, hypertriglyceridaemia, hyponatraemia and haemophagocytosis on bone marrow biopsy). He responded well to initial steroid induction therapy and subsequently mycophenolate mofetil was successfully added as a steroid-sparing agent. This contrasts another similar case of lupus presenting with MAS (pancreatitis, glomerulonephritis, retinal vasculitis) who required cyclophosphamide and plasma exchange following initial poor response to steroids.⁹ There has been a case of HLH secondary to lupus nephritis which did not respond to initial treatment with steroid, tacrolimus and mizoribine, however on the addition of MMF, both the HLH and nephritis improved.¹⁰ This demonstrates the spectrum and variety of clinical presentations and the need for tailored treatment approaches.

MAS in the context of other autoimmune diseases such as systemic juvenile idiopathic arthritis has also been treated very effectively with the IL-1 receptor antagonist, anakinra.¹¹ But its use in the context of MAS secondary to SLE has not been well documented.

Table 1.

Laboratory findings more consistent with SLE flare versus MAS

	SLE flare	MAS
Raised ferritin	+	++++
Elevated LDH	+	++++
Raised triglycerides	+	++++
Low complement	++++	+
Elevated anti-dsDNA antibodies	++++	+
Thrombocytopenia	++	++
Anaemia	++	++
Leucopenia	++	++

LDH, lactate dehydrogenase; MAS, macrophage activation syndrome; SLE, systemic lupus erythematosus.

A generic approach to treating secondary MAS would be to initiate corticosteroids and depending on the severity of the illness, intravenous immunoglobulin. A recent review of HLH has outlined a useful treatment algorithm that can be referred to alongside multidisciplinary team meetings which are often required when treating such unwell and complex patients.¹²

Patient’s perspective.

Illness—especially critical illness accompanied by a diagnosis of something with a 40% mortality rate—is a very scary experience.

Your own body becomes an alien thing and the complete loss of control over your health, drug reactions and pain are basically life-altering.

Starting with a mysterious—and increasingly severe—parotid gland inflammation, leading to ever higher levels of illness and malaise, I ended up in accident and emergency department (A&E) just before Christmas with an infection that no one in the National Health Service (NHS) or indeed an army of private specialists could diagnose. All I knew was that my whole body felt like it was on fire while my limbs had seized up in such severe pain that I practically had to be carried into A&E.

That was followed by a severe allergic reaction to an antibiotic that was used to treat me, eventually ending up with a diagnosis of macrophage activation syndrome. Something much bigger than the relatively quiet lupus I’d lived with for years.

Over a year later, my journey to recovery and wellness is still underway. My physical health has been affected in a way I never imagined possible. I lost nearly two stone and just as I thought I was getting better, I got severe vasculitis in my hands and feet, which has lasted almost a year. The pain was excruciating, my skin was raw and my hair fell out.

The impact on emotional and mental well-being was inevitable; and I am grateful everyday for the incredible support and love I have had from family, friends and my employers. My story would have ended very differently without it.

Above all, I am blown away by the care and support I have received from every single healthcare professional who looked after me whether as an in-patient or otherwise. I have had more blood tests, biopsies and pain than I can keep track of—and the kindness and warmth of every doctor, nurse, phlebotomist and even the hospital staff wheeling patients to and from a battery of tests—has been remarkable. The specialists treating me have shown respect, kindness and compassion always. Patience when I was falling apart, and gentle firmness when I needed it. I had the option of going private but chose not to, because of how secure I felt with the care I was receiving.

Healthcare is about so much more than diagnosis and treatment. I will always be grateful for those at the front lines of our NHS—however flawed it may be—to whom this is a vocation and not just a job. Thank you.

Learning points.

• Macrophage activation syndrome (MAS) is a rare but life-threatening complication of autoimmune rheumatic disorders such as systemiclupus erythematosus.

• Clinical features of MAS and lupus flare may be indistinguishable, but refer to table 1, below, to help distinguish using laboratory findings.

• A high index of suspicion is key to attaining an early diagnosis.

• Early diagnosis and judicious monitoring may help manage MAS and lupus flare effectively with mycophenolate and corticosteroids.