Hemophilia A (HA) is a serious inherited bleeding disorder resulting from a deficiency of coagulation factor VIII (FVIII). Replacement therapy with intravenous infusion of FVIII can be associated with treatment failure in approximately one-third of patients secondary to the development of neutralizing alloantibodies (inhibitor). Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that binds factor IXa and factor X and mimics FVIII. It has been licensed in many countries for the treatment of patients with HA with and without inhibitors with a favorable efficacy and safety profile. A 7-year-old child with severe HA and FVIII inhibitors, refractory to immune tolerance therapy, developed hematuria with nephrotic-range proteinuria after the first dose of emicizumab and subsequently also after a second dose 6 weeks later, which was associated with mild and transient leukopenia. Renal biopsy revealed a pattern of a full-house lupus nephritis. The patient fully and spontaneously recovered between 2 weeks after symptoms onset. In this report, we provide insights on a new and so far unreported renal complication associated to emicizumab treatment. Although emicizumab offers significant benefits for patient with HA, clinicians should be aware of this rare and potential serious renal adverse effect.

Hemophilia A (HA) is a genetic condition with an X-linked recessive inheritance pattern characterized by recurrent and, in some cases, severe bleeding secondary to a reduced level of clotting factor VIII (FVIII). FVIII replacement is the mainstay of treatment of HA1 ; however, FVIII replacement therapy can be associated with treatment failure in approximately one-third of patients because of the development of neutralizing alloantibodies (FVIII inhibitors).2  Furthermore, the efficacy of traditional bypassing agents (recombinant activated factor VII or activated prothrombin complex concentrate) for acute bleeding or prophylactic treatment remains suboptimal.3  Recently, new nonfactor therapies have been developed to address the unmet needs of patients with HA with and without inhibitors.4 

Emicizumab (Hemlibra; Roche, Basel, Switzerland) is a recombinant, humanized, bispecific monoclonal antibody that bridges activated factor IX and factor X to restore the function of missing activated FVIII.3  Emicizumab treatment is not affected by the presence of FVIII inhibitors.3  It is administered subcutaneously with an interval of once every 1, 2, or 4 weeks.3,5,6  Clinical studies in adults and children revealed that emicizumab is well tolerated and improves the quality of life of patients with HA, with a significant reduction of the rate of bleeding episodes, especially in patients with FVIII inhibitors.3,57  The most common adverse effect related to emicizumab administration is self-limited skin reaction at the site of injection; however, other more serious adverse events (including deaths) have been reported as well.3,58  Thrombotic microangiopathy (TMA) is the only renal complication reported so far.3  Of note, all patients with TMA received, concomitantly with emicizumab, infusions of activated prothrombin complex concentrate for breakthrough bleeding.3  We hereby report the first case of a biopsy-proven full-house lupus nephritis induced by emicizumab in a child with severe HA.

A 7-year-old boy with severe HA associated with the presence of FVIII inhibitors (>5 Bethesda units) presented to our clinic for recurrent soft tissue bleeding refractory to treatment with bypassing agents. Thus, a clinical decision was made to treat him with emicizumab. His past medical history was otherwise unremarkable, and specifically, he had not manifested any renal or autoimmune disorder symptoms, signs, or laboratory findings. His family history was unremarkable for renal and/or autoimmune disorders. Written consent from his parents was obtained for publication of this case.

According to the prescribing information, an initial loading dose of 3 mg/kg was administered by subcutaneous injection. Three days after this first injection, the child developed an episode of gross asymptomatic hematuria. Urinalysis confirmed the presence of glomerular hematuria associated with nephrotic-range proteinuria (urinary protein/creatinine ratio: 1147 g/mol). Blood tests revealed mild iron-deficient microcytic anemia (hemoglobin: 94 g/L), unchanged from previous hemoglobin levels. The following laboratory test results were all within normal limits: lactate dehydrogenase (185 U/L, normal value [NV]: 140–280); haptoglobin (1.38 g/L, NV: 0.3–2.0); complement component 3 (0.87 g/L, NV: 0.75–1.4); complement component 4 (0.24 g/L, NV: 0.10–0.34 g/L); hemolytic complement activityis 98% (NV: 70–140); soluble complement complex C5b-C9 (136 ng/mL, NV: 127–303); and complemet component 1q (184 mg/L, NV: 118–224). The serum creatinine and the cystatin C level were in the normal range at 31 μmol/L and 0.73 mg/L, respectively. Renal Doppler ultrasound revealed normal renal parenchyma with normal renal perfusion. The diagnosis of drug-induced interstitial nephritis was initially suspected. The patient recovered spontaneously without any additional treatment, with complete normalization of his urinalysis after 3 days. A drug-induced lymphocyte stimulation test revealed a mild increase of granzyme B secretion (a serine proteinase expressed by T cells) after incubation with emicizumab.

Emicizumab was considered to be an important treatment option for this patient; thus, after discussion of the risk and benefits of repeating a loading dose of emicizumab with the parents, a decision was made to rechallenge the patient 6 weeks after the initial dose. After the second dose of emicizumab, daily urinalysis was performed. One week after the second dose of emicizumab, the child developed abundant microscopic glomerular hematuria associated with nephrotic-range proteinuria (urinary protein/creatinine ratio: 239 g/mol), together with a normal serum creatinine and cystatin C levels. Blood results revealed mild leucopenia (3.6 × 109/L) and lymphopenia (1.33 × 109/L) and a stable mild anemia. All other blood tests were normal, including lactate dehydrogenase and haptoglobin. In addition, a direct antiglobulin test was performed, and the result was negative.

A renal biopsy, under hemostatic control with 90 μg/kg body weight per dose of recombinant activated factor VII, was performed. It revealed mesangial hypercellularity associated with mesangial and membranous deposits of immunoglobulin variants A, G, and M and of the complement component 1q (Fig 1 A and B). This full-house pattern of deposits was localized by electronic microscopy within mesangium and subendothelial areas (Fig 1C). Immunoglobulin G4, complement complex C5b–C9, and complement component 3 staining results were all negative. There was no interstitial fibrosis and no interstitial infiltrate.

FIGURE 1

Renal biopsy. A, Light microscopy. Diffuse mesangial hypercellularity (black arrow) is associated with deposits enlarging also the mesangial matrix. No wire-loop deposits or hyaline thrombi were present. (Acid Fuchsin Orange G stain, original magnification ×400). B, Immunofluorescence microscopy. Complement component 1q staining reveals predominant mesangial deposits with some membranous deposits (original magnification ×400). C, Electronic microscopy. Mesangial and subendothelial areas contain dense deposits (white arrow).

FIGURE 1

Renal biopsy. A, Light microscopy. Diffuse mesangial hypercellularity (black arrow) is associated with deposits enlarging also the mesangial matrix. No wire-loop deposits or hyaline thrombi were present. (Acid Fuchsin Orange G stain, original magnification ×400). B, Immunofluorescence microscopy. Complement component 1q staining reveals predominant mesangial deposits with some membranous deposits (original magnification ×400). C, Electronic microscopy. Mesangial and subendothelial areas contain dense deposits (white arrow).

Immunologic workup confirmed normal complement levels of component 3 and component 4. The results for serum autoantibodies against myeloperoxidase, glomerular basement membrane, proteinase 3, phospholipid, histones, and nuclear were all negative, and rheumatoid factor level was normal. In addition, serological investigation results were negative for Cytomegalovirus;  Epstein-Barr Virus; hepatitis A, B, and C; HIV; parvovirus B19; enterovirus; and adenovirus. The patient fully recovered spontaneously without any additional treatment, with a complete normal urinalysis within 4 and 8 days after clinical presentation, respectively. FVIII inhibitor levels were 28, 23.4, and 13.4 Bethesda unit /mL before the first and second injection and 6 weeks after the second injection of emicizumab, respectively. The persistence of high FVIII inhibitor throughout the observation period indicates that the spontaneous resolution of hematuria is not due to its disappearance.

We report an unexpected case of drug-induced full-house lupus nephritis (DILN) secondary to a new monoclonal antibody (emicizumab) treatment of HA. The diagnosis of DILN in this child is based on clinical presentation (recurrence of hematuria and proteinuria after reexposure of the offending drug), together with histologic findings on the renal biopsy. The diagnosis of TMA or tubulointerstitial nephritis has been excluded. Apart from a mild and transient leukopenia and lymphopenia, the child did not show any other symptoms of systemic lupus erythematosus, such as fever, arthralgia, myalgia, serositis, and/or rash.9  Immunologic investigations were unremarkable. In particular, the results for anti–double-stranded DNA antibodies and antinuclear antibodies for histone proteins were negative. After the first emicizumab injection, the patient presented with gross hematuria and nephrotic-range proteinuria (protein/creatinine ratio of 1147 g/mol), with a plasma level of emicizumab (measured by using a modified 1-stage clotting assay with emicizumab calibrator; r2 Diagnostics, South Bend, IN) of 8.2 μg/mL. On the other hand, clinical renal symptoms were much milder after the second dose of emicizumab; however, the plasma level was higher at 17.1 μg/mL. Measurements of emicizumab levels 1, 2, 6, and 10 weeks after the second injection were 17.1, 11.1, 7.3, and 2.0 μg/mL, respectively. Of note, emicizumab level 1 week before the second dose was at 4.1 μg/mL. The interpretation of all these plasma levels allow us to conclude that there is no correlation between disease severity and emicizumab level. In addition, emicizumab does not seem to be actively consumed during this acute renal complication.

Once the offending drug was stopped, the patient recovered completely from his hematuria and proteinuria and his leukocytes and lymphocytes counts were normalized.

The prevalence of drug-induced lupus nephritis is high, with 15 000 to 30 000 cases per year in the United States.10  The most frequently involved drugs are procainamide (15%–20% of cases) and hydralazine (7%–13% of cases).10  Other drugs (ie, antitumor necrosis factor monoclonal antibodies and minocycline) have also been associated with this complication but with a much lower risk (2 per 1000 and 5 per 10 000, respectively).10  Of note, proteinuria is a known adverse effect of several monoclonal antibodies. Infliximab has been reported to induce proteinuria secondary to the development of membranous glomerulopathy.11  More recently, proteinuria and hypertension have been recognized as a serious and not so uncommon adverse effect of antivascular endothelial growth factor therapy.12  Twenty-one to sixty-three percent of patients treated with bevacizumab will present an often mild and asymptomatic proteinuria.13 

Pathogenesis of DILN remains unclear. Serum lupus biomarkers such as antinuclear antibodies that have specificity for histone, anti–double-stranded DNA antibodies, and/or antineutrophil cytoplasmic antibodies proteins14  may be present in some but not all cases.15,16  The production of these autoantibodies in this context may be explained by an abnormal T-cell response and/or a disruption of central T-cell tolerance by the offending drug, leading to the production of reactive T cells.17  In the present case, serological workup for the presence of antinuclear antibodies was normal and the patient displayed no signs or symptoms suggestive of systemic lupus erythematosus before emicizumab treatment. Several cases of seronegative lupus nephritis have been reported in the literature.17,18  However, the underlying pathophysiological mechanisms are still unknown. In the absence of detectable antibodies, we speculate that emicizumab triggered a direct immune response by activating T cells as demonstrated by the lymphocyte stimulation test, which revealed a mild increased of granzyme B secretion (a serine proteinase expressed by T cells) after incubation with emicizumab. There are other possible explanations for this seronegative full-house lupus nephritis. First, the observed acute renal injury may be part of the broad spectrum of idiosyncratic drug reactions, also known as type B reaction. Secondly, levels of autoantibodies could be too low to be detected by our laboratory techniques. Of note, a subset of patients with seronegative full-house lupus nephritis will develop antibodies during long-term follow-up.19  It also remains difficult to exclude that the previous immune tolerance induction modulated the child’s immune system and contributed to the occurrence of this unusual adverse effect to emicizumab treatment and/or to the absence of immunologic lupus markers in this particular condition.

We consider the exposure to emicizumab as the imputable mechanism for the observed renal complication in this child for the following reasons. First, the occurrence of hematuria was temporally related to the exposure to emicizumab treatment, appearing a few days after infusion. Secondly, there was an immediate recurrence of urinary symptoms after reexposure to emicizumab with no other offending drugs. Third, his medical history and laboratory investigations ruled out preexisting lupus nephritis or any other glomerular disease.

On the basis of this case report and also given the importance of emicizumab treatment in patients with HA, we encourage authors of preclinical studies to further investigate the effects of emicizumab on the immune system regulation and response.

We report the first case of an emicizumab-induced, biopsy-proven seronegative full-house lupus nephritis in a child. Although emicizumab has transformed the management and has improved the quality of life of patients with severe HA, especially those with FVIII inhibitors, clinicians should be aware of a rare but potentially severe adverse effect (ie, lupus nephritis), and they should monitor their patient carefully during emicizumab treatment.

We thank all the doctors, nurses, and colleagues who contributed to the clinical management of the patient.

Drs Chehade and Rizzi provided patient care, coordinated and supervised data collection, analyzed and interpreted clinical and laboratory data, designed and wrote the manuscript, and critically reviewed the manuscript for important intellectual content; Drs Rotman and Alberio analyzed and interpreted laboratory results and contributed to the writing of the manuscript; Dr Diezi evaluated pharmacologic aspects and contributed to the writing of the manuscript; Drs Cachat, Beck-Popovic, and Albisetti interpreted data and contributed to the writing of the manuscript; Dr Young interpreted data, contributed to the design and writing of the manuscript, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

     
  • DILN

    drug-induced full-house lupus nephritis

  •  
  • FVIII

    factor VIII

  •  
  • HA

    hemophilia A

  •  
  • NV

    normal value

  •  
  • TMA

    thrombotic microangiopathy

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Alberio has received research support and support for the institutional hemophilia nurse program from Roche unrelated to the current study; Dr Young has received funding from Genentech/Roche unrelated to the current study; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.