Successful rituximab therapy in a lupus patient with diffuse alveolar haemorrhage

Introduction

Diffuse alveolar haemorrhage (DAH) is a life-threatening manifestation occurring in less than 5% of systemic lupus erythematosus (SLE) patients. ¹ Early mortality rates ranging from 20% to 50% are reported in the small published series of the literature. ^1,2 After exclusion of differential diagnosis, specific therapy must be started immediately and usually includes an aggressive immunosuppression regimen associating high-dose steroids and cyclophosphamide (CYC). We report here a case of severe DAH in a young SLE male successfully treated with rituximab (RTX).

Case report

The patient, an 18-year-old White man, was diagnosed with SLE when he was 12. On diagnosis he presented with osteoarticular and skin involvement and classical biological features (positive antinuclear antibodies (ANA) and anti-dsDNA antibodies, and low C3 and C4 complement components). He had no antiphospholipid antibodies. A few months after the initial diagnosis, the patient developed a severe exacerbation, with fever, arthritis and nephritis treated with pulse corticosteroids and CYC. Immediately following the first CYC pulse he developed a severe bronchospasm and pulmonary infiltrates consistent with acute lung injury. At this time, imputability of CYC was retained on the basis of similar described cases in the literature and the patient was contra-indicated for further CYC administration. ³ SLE flare was controlled with corticosteroid treatment associated with mycophenolate mofetil. He developed three others mild articular flares between 2003 and 2008 managed with corticosteroid dose adaptations.

In January 2009, he was admitted to the intensive care unit (ICU) for septic shock secondary to cervical cellulitis. On ICU admission, his immunosuppressive treatment consisted of 15 mg/day of prednisone and 500 mg/day of mycophenolate mofetil. Septic shock was managed with conventional therapy associating fluid resuscitation, antibiotics administration and norepinephrine. He did not develop respiratory failure. Mycophenolate mofetil was withdrawn and prednisone was replaced by 300 mg/day of hydrocortisone. His condition improved rapidly in the next days and he was transferred to the nephrology’s department on day 7 from admission.

He was readmitted to the ICU on day 13 with dyspnoea and haemoptysis. On admission, he had acute respiratory failure that required mechanical ventilation, profound sedation, curarization and nitric oxide treatment. Chest X-ray and computed tomographic scan showed diffuse bilateral alveolar infiltrates (Figure 1) and hemodynamic monitoring demonstrated low capillary wedge pressure consistent with acute respiratory distress syndrome.

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Figure 1

Chest computed tomography at diagnosis showing diffuse alveolar infiltrates.

Bronchoalveolar lavage (BAL) revealed a haemorrhagic return suggesting DAH. Bacterial, viral and parasitic cultures and stains of BAL remained negative. Immunological analyses were consistent with SLE flare: ANA titre was 1/1280, anti-dsDNA antibodies 92.7 IU/ml (normal value, <20 IU/ml), complement C3 28 mg/dl (normal range, 75–146 mg/dl), and complement C4 5 mg/dl (normal range, 15–39 mg/dl), CH 50 40% (normal value, >70%). Haemoglobin level fell from 12 g/dl before admission to 8 g/dl on admission.

The diagnosis of DAH was then considered and the patient received 2 g/day of mycophenolate mofetil and 1 g/day of intravenous methylprednisolone for 3 days, followed by 1 mg/kg/day. In addition, daily plasma exchanges with albumin substitution were administered for 3 days. Despite this treatment, after 6 days, the respiratory condition worsened and the patient required ventilation with 100% FiO₂. At this time, RTX was considered as a salvage therapy. He received 715 mg (375 mg/m²) of RTX at days 6 and 21, with an excellent tolerance. In the days following the first RTX injection, an improvement of his respiratory condition was observed. The patient was progressively weaned from sedation and extubation was allowed at day 20. B lymphocytes CD19-positive cells decreased from 21.1% to 0.1% 10 days after the second RTX injection. He was transferred to the nephrology department under a regimen of prednisolone 70 mg/day and mycophenolate mofetil 2000 mg/day on day 22. Up to now, no further SLE flare has occurred after 15 months of surveillance.

Discussion

This observation supports the hypothesis that RTX could be an alternative to CYC treatment in severe forms of SLE-induced DAH or in CYC-resistant forms of DAH.

The physiopathology of SLE-induced DAH has been poorly studied but is admitted to be an immune complex deposition disease. Histopathologic features include inflammatory cell interstitial infiltration, alveolar necrosis and an acute necrotizing capillaritis. Immune complex deposition (IgG and C3) is usually detected in alveolar and in small vessels walls. ⁴ Data reporting treatment effectiveness and patient’s outcome are scarce and derive from uncontrolled case series. ^1,2 The literature suffers from considerable variability in the timing, dosing and treatment duration. A short time delay between disease occurrence and treatment initiation is crucial to maximize the chances of recovery. Standard regimens are based on a heavy immunosuppression associating high-dose steroids plus CYC and plasma exchange. In this setting, remission is achieved in most patients, but disease relapse and treatment-associated toxicity, particularly sepsis, contribute to the mortality and chronic incapacity. ⁵

Recent advances in SLE physiopathology have identified B-cell activation to take an important place in SLE physiopathology. ⁶ Autoantibody production, cytokine secretion and T–B cell cooperation are some of the functions that are aimed to be suppressed by depletive B-cell targeted therapies in SLE. RTX is a chimeric murine–human monoclonal antibody directed against the specific B-cell CD20 antigen. After RTX treatment, a reduced number B-cells are observed in the days following RTX administration. ⁶ The proposed mechanisms of action of RTX include antibody direct cellular toxicity, complement dependant cytotoxicity and B-cell-mediated receptor apoptosis.

RTX has been used with success in active or refractory SLE manifestations such as SLE vasculitis or SLE nephritis as well as in other autoimmune disease such as refractory idiopathic thrombocytopenic purpura. ^7,8 Two other cases of SLE-induced DAH have been reported to respond to RTX administration, but in contrast to our case, RTX was associated with CYC administration along with other immunosuppressants (Table 1). ^9,10 Patient 1 (Table 1) received RTX for a relapse of DAH treated initially with corticosteroids, plasma exchange and two CYC pulses. For patient 2 (Table 1), RTX was administered concomitantly with a CYC pulse and corticosteroids. In these cases as in ours, a pulmonary improvement was observed in the early days following RTX administration. Although retarded, the lymphotoxicity of a CYC bolus reaches a nadir around the 10th day and one cannot exclude a combined effect of RTX and CYC in these two previous cases. ¹¹ Interestingly, the patients did not relapse DAH or other associated SLE involvement after several months of surveillance despite the lack of CYC maintenance regimen. The mechanisms by which RTX induce early improvement in these patients is unclear. Autoantibody production does not seem to be reduced before 3 months following RTX administration. ¹² Interestingly, early similar improvement has been reported following RTX treatment in a patient with the prototypic autoimmune antiglomerular basement membrane disease. ¹³ One hypothesis is that RTX by depleting circulating B-cells may induce a suppression of cytokine production and an inhibition of T–B cell cooperation.

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Table 1

Rituximab treatment in SLE patients with DAH

Subject	Age yrs	Sex	Disease and treatment course	RTX timing and dosing	RTX associated treatments	Maintenance regimen	Outcome
19	29	F	Methylprednisolone boluses/CYC boluses/PE, mechanical ventilation, extubation on D26, relapse on D34	RTX on D34 every 2 weeks for 6weeks 375 mg/m2 each administration	Prednisone, CYC boluses, PE	Cyclosporine, mycophenolate mofetil, prednisone	No relapse Follow-up duration not specified
210	52	F	Methylprednisolone boluses, non-invasive ventilation on D4, RTX on D5, CYC boluses on D6	RTX on D5 and D22 1000 mg each administration	Prednisone, CYC boluses	Prednisolone	No relapse at month 16
Present case	18	M	Methylprednisolone boluses, mycophenolate mofetil, PE, mechanical ventilation, RTX on D6	RTX on D6 and D21 750 mg (375 mg/m2) each administration	Prednisone, mycophenolate mofetil	Prednisone, mycophenolate mofetil	No relapse at month 15

This observation suggests two potential benefits of RTX in SLE-induced DAH. The first is an early effect that may contribute to faster pulmonary recovery in severe forms or in CYC-resistant forms of SLE-induced DAH. The second is the long-term remission maintenance of the disease with the use of RTX as a cytotoxic sparing agent. Given its safety profile, RTX should be evaluated in further studies for the initial treatment of severe forms of SLE-induced DAH.