Eculizumab therapy and complement regulation in a case of resistant catastrophic antiphospholipid syndrome

Abstract

Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening form of antiphospholipid syndrome characterised by diffuse arterial and venous thrombosis, in the presence of positive antiphospholipid antibodies. The multiple sites of thrombosis in small, medium and large vessels progress to multiorgan failure, accounting for the high mortality rate associated with CAPS. Unregulated complement activation is increasingly recognised as critical to the pathogenesis of CAPS. Early diagnosis is essential to initiate prompt life-saving treatment with the triple therapy of anticoagulation, immunosuppression and either plasmapheresis or intravenous immunoglobulin. Among other immunosuppressive agents, eculizumab, a complement inhibitor has demonstrated efficacy in treatment-resistant cases.

We report an instructive case of a woman presenting with both clinical and laboratory findings consistent with primary CAPS, resistant to initial treatment and responsive to eculizumab, with emphasis on genetic testing and implications for future therapy.

Background

Antiphospholipid syndrome (APS) is an autoimmune disorder presenting with diffuse arterial and venous thrombosis, and positive antiphospholipid antibodies.¹ APS can be either primary or secondary to autoimmune diseases including systemic lupus erythematosus (SLE).¹ Catastrophic antiphospholipid syndrome (CAPS) is a subtype of APS, defined by the following four criteria: involvement of three or more organ systems; occurring within less than a week; with histological confirmation of microvascular thrombosis; the presence of antiphospholipid (aPL) antibodies on two occasions more than 6 weeks apart.^2–4 Definite CAPS diagnosis requires all four criteria, and probable CAPS includes three criteria.^{2 4 5} CAPS is a rare life-threatening disease developing in approximately 1% of patients with APS and mortality as high as 50%.⁶ Early recognition has been associated with improved mortality.⁵

Studies have demonstrated that unregulated complement activation is critical to the pathophysiology of CAPS, and 60% of patients may have underlying germline variants of complement regulator genes.^{7 8} Complement inhibition with eculizumab has been reported as a treatment for resistant disease.⁷

Case presentation

A woman in her late adolescence presented to a regional hospital with cardiogenic shock, a pulmonary embolus, oligoanuric renal failure and severe thrombocytopenia following a recent upper respiratory tract infection. On examination, she was hypotensive with a systolic blood pressure of 60 mm Hg, tachycardic with a heart rate of 110 beats per minute, oxygen saturations of 84% on room air and a respiratory rate of 26 breaths per minute. She was diaphoretic with dry mucous membranes and pale conjunctiva. Jugular venous pressure was normal, chest auscultation showed bibasal crackles, dual heart sounds with no murmur and no peripheral oedema. Livedo reticularis was noted over the lower limbs.

Her medical history included previous positive lupus anticoagulant serology in the context of a self-resolving episode of chorea at age 14 and two spontaneous miscarriages (at 14 and 16 weeks gestation).

She was admitted to intensive care and required transfer to a tertiary centre.

Investigations

On admission, she had laboratory evidence of anaemia (haemoglobin 75 g/L), elevated white cell count at 27.9×10⁹/L, thrombocytopenia (platelets 31×10⁹/L), a serum creatinine of 648 µmol/L with an indication for dialysis of hyperkalaemia (potassium 6.1 mmol/L) and uraemia (urea 55.9 mmol/L, results trend in figures 1 and 2); C reactive protein of 437 mg/L and erythrocyte sedimentation rate of 102 mm/hour. The international normalised ratio (INR) was 1.4, which was corrected with INR mixing studies to 1.1; her activated partial thrombin time was 75 seconds (no correction with mixing studies, suggesting the presence of lupus anticoagulant). Fibrinogen was elevated at 5.2 g/L, and D-dimer was elevated at >20.00 mg/L (reference range <0.5mg/L). There was evidence of hypocomplementaemia with C3 0.5 g/L (0.9–1.80 g/L) and C4 0.03 g/L (0.16–0.47 g/L). Haemolysis makers were negative; normal serum haptoglobin at 2.70 g/L, normal bilirubin of 11 µmol/L, inappropriately normal reticulocyte count of 1.9×10⁹/L and no schistocytes on the blood film, lactate dehydrogenase was elevated at 992 U/L in keeping with an acute inflammatory response. Urinalysis had no presence of leukocytes, erythrocytes or proteinuria, and negative culture. A CT pulmonary angiogram confirmed multiple segmental and subsegmental pulmonary emboli to left upper lobe and lingula, and right middle lobe, there was bilateral ground glass opacity and bilateral small pleural effusions.

Figure 1.

Complement and platelet counts throughout the presentation in relation to administration of eculizumab.

Figure 2.

Renal function throughout the presentation.

Cardiovascular involvement included an elevated high sensitivity troponin 2296 ng/L, peaking at 5014 ng/L. Her ECG demonstrated a sinus tachycardia, with features of left ventricular hypertrophy. A transthoracic echocardiogram estimated the left ventricular ejection fraction (LVEF) to 31%, in severe global systolic dysfunction complicated by moderate functional mitral regurgitation.

Prophylactic anticoagulation with subcutaneous heparin was initiated at 5000 units every 12 hours given thrombocytopenia, and high dose intravenous methylprednisolone for the working diagnosis of CAPS, with extensive thrombosis.

On further investigation, a Nuclear Medicine Renogram study reported a pattern suggestive of severe acute tubular necrosis, with no evidence of large vessel occlusion. Triple aPL antibody positivity with anticardiolipin antibody (IgM 25 U/mL and IgG 147 U/mL, laboratory normal reference range <20 U/mL), lupus anticoagulant (lupus anticoagulant ratio 2.0, normal reference range <1.2) and anti-β2 glycoprotein (IgG >160 U/mL, laboratory reference range <20 U/mL). Autoimmune serology, antinuclear antibody (ANA), extractable nuclear antigen (ENA), antidouble stranded deoxyribonucleic acid (anti-dsDNA), rheumatoid factor, anticitrullinated peptide antiby and ADAMTS13 activity were normal. Intravenous immunoglobulin (IVIg) (2 g/kg) induction was given for the treatment of presumed primary CAPS.

On day 6 of her presentation, the patient had a progression of symptoms; a unilateral oedematous left arm and generalised abdominal pain. Repeat imaging confirmed extensive thrombosis: left upper limb cephalic vein thrombus, splenic and renal infarct confirmed via a CT abdomen and pelvis with contrast, and vascular tunnelled central access catheter-related thrombus, all of which had developed despite low-dose heparin.

Differential diagnosis

In the presence of multiorgan dysfunction, disseminated thrombosis, symptoms evolving over 1 week, the presence of aPL antibodies and normal ADAMTS13 activity, a diagnosis of probable primary CAPS was made. The differential diagnosis for CAPS is broad as sepsis, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome and disseminated intravascular coagulation (DIC) share many overlapping features and may present concurrently.⁵ However, extensive investigation for an infectious cause, lack of features of thrombotic microangiopathy and hyperfibrinogenaemia ruled these unlikely. The patient continued on heparin and methylprednisolone and was given intravenous cyclophosphamide 500 mg with dosing according to Eurolupus protocol (at which time a diagnosis of SLE was under consideration).⁹ Subcutaneous goserelin was used for fertility preservation. Four cycles of plasma exchange were administered. A tissue diagnosis was not pursued due to bleeding risk.

Treatment

The patient deteriorated, with worsening thrombocytopenia and ongoing hypocomplementaemia (C3 0.56 g/L and C4 0.09 g/L). On day 7 and 8 of the presentation, the patient developed acute gastrointestinal bleeding with hypovolaemic shock, requiring two embolisations and blood product replacement (including platelets). There was concern that this represented a life-threatening deterioration for the patient and failure of initial treatment. Consequently, on day 11 of the presentation, weekly eculizumab 900 mg intravenous infusion was given for a total of 4 weekly doses. Relevant immunisations for encapsulated organisms were administered prior to the infusion, and antimicrobial prophylaxis was given with intravenous ceftriaxone for the first 2 weeks, followed by oral ciprofloxacin (a penicillin allergy precluded the use of amoxicillin). Following the first dose of eculizumab, a plateau of illness was observed with improvement of the nadir platelet count of 13×10⁹/L to 85×10⁹/L over 2 weeks and normalised complement (C3 0.88 g/L and C4 0.17 g/L). Renal replacement therapy was ceased. The patient was transitioned to high-dose prednisolone and oral hydroxychloroquine, ceased heparin, transitioned to enoxaparin and later changed to warfarin (target INR 2–3). The patient completed six cycles of cyclophosphamide according to the Eurolupus protocol (goserelin every second cycle for fertility preservation) as ANA-negative SLE had a lower probability differential that may have contributed to the severity of her presentation.⁹

Outcome and follow-up

At 9 months follow-up, there are no further episodes of thrombosis; with ongoing anticoagulation and immunosuppression (prednisolone 5 mg/day and hydroxychloroquine 200 mg/day). The patient’s renal function recovered to an estimated glomerular filtration rate (eGFR) of 42 mL/min and creatinine of 152 µmol/L. Cardiac function has slowly improved to LVEF 44%, cardiac MRI reported LVEF of 46% 6 months after initial presentation. MRI brain reported microinfarcts to bilateral supratentorial on high T2/fluid attenuated inversion recovery (FLAIR) signal attributed to her original presentation. On repeat aPL antibodies, anticardiolipin remained positive (IgG 51 U/mL, IgM 9 U/mL, normal laboratory reference range <20 U/mL), $\beta$2 glycoprotein positive (305 U/mL IgG, reference range normal <20 U/mL) and lupus anticoagulant positive (lupus anticoagulant ratio 2.1, normal reference range <1.2). Platelet count and complement levels had normalised.

To assist discussions on future planning for renal transplantation and pregnancy, genetic testing was performed for exon genes associated with complement activation and regulation (CFH, CFB, CFI, CFD, CFHR1, CFHR2, CHGR3, CFHR4, CFHR5, C3, CD46, MCP, THBD, CR1 and DGKE). These genes were negative for variants of clinical significance.

Discussion

CAPS is a rare subtype of APS. According to the CAPS registry, the major systems involved are renal (71%), respiratory (64%), central nervous system (62%), cardiovascular (51%) and cutaneous (50%), followed by gastrointestinal manifestations.⁵ The most common laboratory features include severe thrombocytopenia, schistocytes, microangiopathic haemolytic anaemia and DIC, found in 67%, 22%, 16% and 11% of patients with CAPS, respectively.¹

A precipitating event is found in two-thirds of CAPS presentations, including infection, malignancy, recent surgery, pregnancy, medications and flares of other autoimmune conditions.¹⁰ These precipitating factors trigger the thrombotic cascade and rapid evolution of symptoms.¹⁰

Patients with CAPS harbour a high rate of germline variants in complement regulator genes; however, these are only found in 60% of cases.¹¹ Observational studies have identified a similar rate of germline mutations in complement regulator genes to those with atypical haemolytic uraemic syndrome, which is conceptualised as the traditional complement-mediated thrombotic microangiopathy.¹¹ Although our patient had no detectable complement gene regulator mutation, there is still a potential for unknown variants yet to be discovered, and epigenetics is not accounted for in germline mutation testing.

According to the ‘two-hit’ hypothesis, the germline mutation and aPL antibodies serve as the ‘first hit’, although with incomplete penetrance, so that a complement trigger is required as the ‘second hit’ in order to manifest a severe clinical phenotype (figure 3).¹¹

Figure 3.

Diagram of the pathogenesis of catastrophic antiphospholipid syndrome (CAPS), with ‘first and second hit’ combining to activate complement pathway, demonstrating the role of eculizumab in inhibiting the conversion of C5 to C5a and C5b and the mechanism of eculizumab being used as a treatment for CAPS.

Initial treatment for CAPS involves identifying and removing the precipitant, and triple therapy consisting of anticoagulation, corticosteroids and plasma exchange or IVIg.¹ Plasma exchange is preferred over IVIg for patients with microangiopathic features or renal involvement.¹² The use of IVIg is considered over plasma exchange when there is more of a predominance of immune-mediated thrombocytopenia.¹

Management options for resistant CAPS include escalation of immunosuppression, with cyclophosphamide, rituximab or eculizumab.^{12 13} Cyclophosphamide may be chosen where CAPS is secondary to SLE, alongside other disease-specific therapies including hydroxychloroquine.^{13 14} Cyclophosphamide was initiated in our patient while her diagnostic work-up was in progress, with an initial suspicion for underlying SLE although serology was later negative. A retrospective cohort analysis of kidney transplant recipients has also identified the mechanistic target of the rapamycin complex pathway in chronic vascular lesions for APS nephropathy.¹⁵ There are emerging data for the use of sirolimus in non-transplant recipients.¹⁶ Barriers to sirolimus use consider drug–drug interactions and side effects, which are particularly more pronounced with chronic kidney disease (eGFR <30 mL/min/1.73 m²), for this reason sirolimus was not used in this case.¹⁶

Eculizumab is a monoclonal antibody against C5, inhibiting the breakdown of C5 to C5a and C5b in the complement pathway.¹ Eculizumab has been proposed as a targeted treatment for those patients who have resistant CAPS due to the pathogenic association with complement activation.¹ Eculizumab has been successfully used in cases of recurrent or resistant CAPS, especially those where thrombotic microangiopathy (TMA) is prominent, with partial or complete response in 75% of patients.^{7 17} From case studies, eculizumab may have a key role for treatment when massive aPL-induced complement activation is present, particularly in the presence of thrombocytopenia.^{1 7}

There is substantial variation in reported dose, frequency, treatment duration and time of eculizumab initiation, although it has been broadly effective when used.⁷ Guidelines for eculizumab recommend immunisation for encapsulated organisms prior to administration.⁷ Our patient received antimicrobial prophylaxis due to the concern of significant immunosuppressive therapy and the splenic infarction secondary to CAPS.

Rituximab is an anti-CD20 monoclonal antibody resulting in B-cell depletion and possibly increasing regulatory B-cell proportion, to decrease the pathogenic immune spiral.^{12 13} However, this process can take weeks for peak clinical effect, as opposed to eculizumab.¹⁸ Rituximab has been shown to improve microvascular manifestations of CAPS including severe thrombocytopenia, skin ulcers, nephropathy and cognitive dysfunction.¹⁹ In the CAPS Registry, rituximab was used in treatment-resistant cases with 75% response rates.²⁰ However, rituximab does not directly target complement dysregulation which is likely to have a central role in CAPS.

The impact of CAPS on future renal transplantation is an important consideration in patients who progress to end-stage renal failure. There is a high rate of early graft loss due to thrombosis or TMA in patients with CAPS and perioperative anticoagulation may reduce the risk of graft loss.¹² The 10-year graft survival is lower in transplant recipients with APS, compared with those without APS.¹² Limited evidence from case series prompts the hypothesis that eculizumab use in the peritransplant and post-transplant period may improve graft survival.^{18 21 22}

Learning points.

• Complement activation has a central role in the pathogenesis of catastrophic antiphospholipid syndrome (CAPS).

• This case adds supportive evidence for targeting complement inhibition in the treatment of severe or resistant CAPS.

• Genetic testing and counselling for complement regulator defects is an evolving consideration for patients presenting with CAPS

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).