Severe refractory idiopathic warm autoimmune haemolytic anaemia responsive to complement inhibition with eculizumab

Abstract

We report a case of severe idiopathic warm autoimmune haemolytic anaemia (wAIHA) which was initially poorly responsive to treatment with corticosteroids, intravenous immunoglobulin, mycophenolate mofetil and rituximab, and required transfusion of more than 30 units of red cells over 12 weeks. Off-label use of the terminal complement pathway inhibitor, eculizumab, led to rapid amelioration of the haemolysis, presumably by the inhibition of an intravascular component, and allowed time for slower acting immunosuppressive agent to take effect. This novel approach warrants further evaluation, given the poor prognosis of multirefractory wAIHA.

Background

Warm autoimmune haemolytic anaemia (wAIHA) accounts for 65% of autoimmune haemolytic anaemia (AIHA)¹ and results from autoantibody mediated destruction of red blood cells (RBC), with or without complement activation.^{2 3} The autoantibody is usually IgG, with maximal reactivity at 37°C. Secondary causes include malignancy (particularly B cell), and autoimmune disease, but about 50% of cases are idiopathic. There is sparse evidence on which to base management decisions, though consensus guidelines do exist.¹ Corticosteroids are usually first-line treatment, with intravenous immunoglobulin or plasma exchange as options in severe/life-threatening cases. Red cell transfusions are avoided as far as possible. Second-line and third-line treatments include rituximab, splenectomy and a variety of other immunosuppressive agents.^{1 4 5} Cases refractory to several lines of therapy are associated with a poor prognosis so new treatment approaches are of particular interest.⁶ Here, we report a rapid clinical response to novel off-label use of the terminal complement pathway inhibitor eculizumab in a case of severe refractory idiopathic wAIHA.

Case presentation

A 53-year-old woman presented to the emergency department with a 2-week history of fatigue, dyspnoea on exertion, dizziness and yellow discolouration of her skin and sclera. She had suffered a likely viral upper respiratory tract infection a week prior, having previously been fit and well. Medical history included Still’s disease in adolescence, vitiligo for over 30 years, hypothyroidism for about 20 years, hypertension and occasional migraines. Medications included bendroflumethiazide and levothyroxine. On examination, she was obviously jaundiced. There was no evidence of lymphadenopathy or hepatosplenomegaly.

Investigations

Laboratory tests revealed a haemoglobin (Hb) of 5.9 g/dL, with a reticulocytosis at 14.7%, elevated bilirubin at 85 μmol/L (reference range 0–20 μmol/L)) and elevated lactate dehydrogenase (LDH) at 690 IU/L (reference range 135–214 IU/L). Haptoglobin was undetectable. The peripheral blood film was consistent with haemolysis (polychromasia, spherocytosis, nucleated red cells). Direct antiglobulin test (DAT) was positive for IgG (2+) but negative for C3d. Urinary haemosiderin was positive. Paroxysmal nocturnal haemoglobinuria (PNH) screen was negative. CT thorax/abdomen/pelvis and bone marrow aspirate and trephine did not reveal any secondary cause. Hepatitis B and C, HIV, EBV, mycoplasma and syphilis serology were negative. Antinuclear antibody, anti-extractable nuclear antigen antibody, and anti-double stranded- DNA antibody screening was negative.

Differential diagnosis

The diagnosis of AIHA was made on the basis of the haemolytic picture on routine bloods (anaemia, reticulocytosis, raised LDH, hyperbilirubinaemia and low haptoglobin) with a positive DAT. The spherocytosis and polychromasia on blood film were also consistent (marked spherocytosis with a negative DAT would be suggestive of hereditary spherocytosis). In wAIHA, the DAT is positive for IgG ±C3, while isolated C3 positivity would confer a diagnosis of cold AIHA.¹ Urinary haemosiderin positivity suggested a degree of intravascular haemolysis (in addition to extravascular haemolysis which is usually the predominant mechanism in wAIHA). The negativity of the other investigations suggested a primary (idiopathic) rather than secondary wAIHA.

Treatment

Standard first-line treatment was initiated, with corticosteroids (prednisolone 1 mg/kg (64 mg) one time a day), in addition to folic acid, with omeprazole as gastroprotection. The severity of the haemolysis necessitated transfusion of 6 units of red cells over the following week to treat severe anaemia symptoms. However, by day 7, the Hb was only 9.0 g/dL and there had been no reduction in haemolysis (in fact reticulocyte count, bilirubin and LDH had all increased further). By day 11, Hb had fallen to 7.6 g/dL and symptoms necessitated a further transfusion but prednisolone had to be reduced to 40 mg/day because of intolerance. In view of ongoing brisk haemolysis, intravenous immunoglobulin was administered (1 g/kg/day for 2 days). This had no clear clinical impact by day 14, when Hb was 8.4 g/dL and bilirubin 121 μmol/L. Rituximab (375 mg/m²) was initiated on day 15. Three further doses were given, on days 22, 27 and 32. By day 30, there was still no obvious improvement: Hb was 7.9 g/dL with an ongoing transfusion requirement, and LDH and bilirubin remained markedly elevated (see figure 1). Given the severity of the haemolysis, rather than continuing to wait for a rituximab response, mycophenolate mofetil (MMF) (1 g/day) was introduced as fourth-line treatment on day 31.

Figure 1.

Response of warm autoimmune haemolytic anaemia to eculizumab. (Panel A) Left-hand Y axis shows haemoglobin (Hb, g/L, red line), bilirubin (µmol/L, yellow line) and reticulocyte count (%, dotted red line) over the course of the illness with lactate dehydrogenase (LDH) (IU/L, blue line) on the right-hand Y axis. (Panel B) Bar chart indicating the record of blood transfusions (units of red cells; red bars) along with doses of rituximab (375 mg/m²×4; black bars) and eculizumab (900 mg/m² weekly for the first four doses, followed by 1200 mg/m² fortnightly for a further eight doses; blue bars). Other therapies included prednisolone days 1–90 and mycophenolate mofetil from day 31 until 11 months post remission.

By day 50, there was still no obvious improvement. Haemolytic markers remained significantly elevated (bilirubin 99 μmol/L and LDH 1045 IU/L) and a further 9 units of RBC had been transfused since MMF had been started 19 days prior, bringing the total to 28 units. The patient was unkeen to undergo splenectomy. A compassionate use application for eculizumab was made. After vaccination against Neiserria meningitidis and with appropriate antibiotic prophylaxis, she received eculizumab (900 mg) at weekly intervals, started taking from day 55.

From day 55 onwards, there was a progressive fall in LDH. Only 4 units of red cells were transfused in the 4 weeks that followed (days 55–83) (compared with 11 units in the 4 weeks prior to that (days 27–55)). By the fifth eculizumab infusion (day 83), bilirubin had fallen to 70 μmol/L and LDH to 398 IU/L. Eculizumab dosing was switched to 1200 mg fortnightly. Only 2 further units of RBC were transfused (day 85). Prednisolone was stopped on day 90, having weaned from 40 mg over an 8-week period. By day 153, a complete haematological response had been achieved. A final two doses of eculizumab were subsequently given, bringing the total to 12.

Outcome and follow-up

No side effects or infectious complications of eculizumab occurred. After 11 months of haematological remission, MMF was stopped, with no recurrence of haemolysis. Our patient currently remains well, with the total duration of remission now at 19 months.

Discussion

The use of four or more therapies in wAIHA has been identified as a predictor of fatal outcome.⁶ The severity of this case, as evidenced by the ongoing high transfusion requirement despite corticosteroids (although at reduced dose), intravenous immunoglobulin, rituximab and MMF, justified a novel approach.

Eculizumab is a monoclonal antibody against complement protein C5. It prevents the activation of the terminal complement pathway and formation of the membrane attack complex (MAC). It is licensed in PNH⁷ and atypical haemolytic uraemic syndrome.⁸ However, a recent review⁹ cites successful off-label use in at least 25 conditions including other thrombotic microangiopathies and hyperhaemolysis in sickle cell disease.

There are some limited data on the use of eculizumab in AIHA, but not to our knowledge in primary wAIHA. Efficacy in cold agglutinin disease (CAD) was reported in a phase II trial of 13 patients,¹⁰ as well as two case reports.^{11 12} Mechanistically, one would postulate a smaller role for eculizumab in IgG-mediated wAIHA than in CAD (the latter being complement mediated, via IgM). IgG is a less potent activator of complement than IgM, but C1q can bind to IgG-coated RBCs leading to formation of C3b via the classical complement pathway. Activation of C5 and MAC-mediated intravascular haemolysis can ensue,^{2 3} and would be halted by C5 inhibition. However, the predominant mechanism of haemolysis is extravascular haemolysis via phagocytosis/antibody-dependent cell-mediated cytotoxity of warm antibody coated (and also C3b-opsonised) red cells in the reticuloendothelial system,^{2 3} which C5 inhibition would not be expected to prevent.

There are however two published reports of clinical efficacy of eculizumab in wAIHA, in IgM-mediated wAIHA secondary to Churg-Strauss syndrome,¹³ and in refractory IgG-mediated wAIHA secondary to Waldenstrom macroglobulinaemia.¹⁴ Both cases had evidence of complement activation, with DAT positivity for C3d.

Our case is striking because it is the first documented case of eculizumab efficacy in idiopathic, as opposed to secondary, wAIHA, and also because the DAT was repeatedly negative for C3d. Despite this, the presence of urinary haemosiderin implied the presence of intravascular haemolysis (presumably MAC driven), providing a therapeutic rationale for C5 inhibition. The lack of C3d positivity on DAT may have been an assay sensitivity issue, but C3 independent intravascular immune haemolysis has previously been postulated.^{15 16}

The clinical improvement in terms of LDH, bilirubin and Hb after initiation of eculizumab was striking. Mechanistically, eculizumab would not be expected to terminate the mainly extravascular haemolysis of wAIHA. However, in this case, it presumably inhibited the intravascular component, ameliorating the overall severity of haemolysis, and acting as a bridging therapy while rituximab (median time to response 3–6 weeks¹), and MMF (3–4 months¹) took effect. This reduced transfusion requirements and allowed rapid tapering of steroids, minimising associated adverse effects. Given the poor prognosis of multirefractory wAIHA, further exploration of this novel therapeutic approach is warranted.

Patient’s perspective.

I have always been a healthy, fit and active woman and I became seriously ill with wAIHA in May 2016. The rapidness and deterioration of my health was extreme and very scary. It was life threatening and a shock to all those who know me well, to see me so ill and deteriorate so quickly. At times I could barely stand up and walk and talking made me breathless.

Although the hospital staff were wonderful, none of the normal treatments for this condition were working; this painted a very bleak picture for me. Once I started the eculizumab, I noticed an improvement in my health and it continued to improve as I had more treatment. The blood transfusions eventually became less as I improved. I was aware it might not work but I cannot express how privileged I feel to be given the chance to trial it. In my view, this treatment saved my life.

I am now very well, working full time and back to all my normal recreational activities; swimming/cycling, yoga and gym etc. The wAIHA now seems like a nightmare from the past.

I feel reassured that if I ever have this condition again that there is treatment available to me that does work.

Learning points.

• Warm autoimmune haemolytic anaemia (wAIHA) carries a poor prognosis when refractory to several lines of therapy.

• In our patient, novel off-label use of eculizumab appeared to rapidly ameliorate severe and refractory haemolysis, presumably by inhibiting a complement-mediated intravascular component.

• The potential for eculizumab to act bridging therapy in cases of severe wAIHA with evidence of complement activation while other immunosuppressives take effect warrants further evaluation.