Lupus (2015) 24, 756–759


Rituximab: an emerging treatment for recurrent diffuse alveolar hemorrhage in systemic lupus erythematosus JR Tse1, KE Schwab1, M McMahon2 and W Simon1 Department of Medicine, 1Division of General Internal Medicine; and 2Division of Rheumatology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA

Diffuse alveolar hemorrhage (DAH) is a rare manifestation of systemic lupus erythematosus (SLE) and is associated with high mortality rates. Treatment typically consists of aggressive immunosuppression with pulse-dose steroids, cyclophosphamide, and plasma exchange therapy. Mortality rates remain high despite use of multiple medical therapies. We present a case of recurrent DAH in a 52-year-old female with SLE after a deceased donor renal transplant who was successfully treated with rituximab. Our report highlights the pathophysiologic importance of B-cell-mediated immunosuppression in SLE-associated DAH and suggests that rituximab may represent a viable alternative to cyclophosphamide in the treatment of this disease. We also review eight other reported cases of rituximab use in SLE-associated DAH. Lupus (2015) 24, 756–759. Key words: Systemic lupus erythematosus; vasculitis; renal lupus


Case report

Diffuse alveolar hemorrhage (DAH) is a rare but potentially fatal complication of systemic lupus erythematosus (SLE). DAH is typically considered in SLE patients with respiratory distress, especially when it is accompanied by an unexplained drop in hemoglobin.1 Once other causes of alveolar hemorrhage are excluded, patients are treated with aggressive immunosuppression. Such treatment regimens classically consist of pulse-dose steroids, cyclophosphamide, and plasma-exchange therapy. However, mortality rates with these therapies remain high with many adverse side effects.1 We present a case of recurrent DAH in a 52-year-old woman with SLE after a deceased donor renal transplant who was treated successfully with pulse-dose steroids, plasma exchange therapy, and rituximab.

The patient was diagnosed with SLE at age 44 after presenting with a malar rash, polyarthralgias, Raynaud’s disease, anemia, positive antinuclear antibodies (ANA), and nephritis. The patient was negative for both double-stranded DNA (dsDNA) and Smith (Sm) antibodies at the time of diagnosis. The patient did not meet criteria for antiphospholipid syndrome (APS), as she did not have a known clinical thrombotic event and had negative APS labs. A few months after diagnosis, she developed end-stage renal disease (ESRD) secondary to lupus nephritis and thrombotic microangiopathy. She was hemodialysis dependent for eight years and tried prednisone, mycophenolate mofetil, and hydroxychloroquine for the management of her SLE. In May 2013, she received a deceased donor renal transplant. She was treated with induction methylprednisolone and thymoglobulin, as well as tacrolimus for maintenance immunosuppression. On postoperative day 4, she developed suddenonset dyspnea, hemoptysis, and pleuritic chest pain. Physical examination revealed tachypnea, tachycardia, and diffuse crackles on auscultation. The patient had an O2 saturation of 51%, and a pre-intubation arterial blood gas (ABG) showed

Correspondence to: Wendy Simon, Department of Medicine, Division of General Internal Medicine, David Geffen School of Medicine at University of California, Los Angeles, 757 Westwood Plaza, Los Angeles, CA 90095, USA. Email: [email protected] Received 21 September 2014; revised: 23 October 2014 accepted 20 November 2014 ! The Author(s), 2014. Reprints and permissions:

Downloaded from at University of Manitoba Libraries on June 9, 2015


Emerging treatment for recurrent diffuse alveolar hemorrhage in SLE JR Tse et al.


acute hypoxemic hypercarbic respiratory failure (pH 7.06; pCO2 69 mmHg; pO2 44 mmHg; bicarbonate 19 mmol/l) that improved immediately post-intubation. Labs were significant for a hemoglobin of 7.4 g/dl, a drop of 1.5 g/dl from the postoperative baseline of 8.9 g/dl, and a peak creatinine of 1.7 mg/dl, an increase from 0.9 mg/dl postoperatively. Rheumatologic labs were notable for ANA >1:1280 and an elevated rheumatoid factor, though anti-dsDNA levels remained normal and C3 levels were only transiently decreased. Chest computed tomography (CT) showed extensive ground-glass opacities and airspace consolidations bilaterally with background interstitial fibrosis. The patient underwent a bronchoalveolar lavage (BAL), which demonstrated hemosiderin-laden macrophages consistent with DAH. A thorough workup to ascertain the etiology of the DAH showed no evidence of pulmonary infections, pulmonary embolism, hypercoagulability syndromes, other rheumatologic diseases, or cardiogenic abnormalities. Given this, the DAH was presumed to be secondary to a lupus flare. The patient received methylprendisolone 500 mg intravenously (IV) daily for three days before transitioning to oral prednisone, plasma exchange for five days, and a total of 100 g intravenous immunoglobulin (IVIG) (25 g for four days). She was also empirically covered with vancomycin, meropenem, and caspofungin before infectious etiologies were ruled out. There was initial discussion about whether to initiate cyclophosphamide or rituximab therapies. However, there was concern about cyclophosphamide toxicity as she became thrombocytopenic to 108,000/ml during her 10th day of treatment. Moreover, given that the patient was clinically improving on her current regimen, a decision was made to continue her treatment course and reconsider additional therapies only if her clinical status were to worsen. The patient gradually improved, with resolving dyspnea, chest pain, and hemoptysis. She was discharged home on a prednisone taper one month after initial transplantation with a hemoglobin of 9.1 g/dl. Given her recent renal transplant, she was also discharged on daily mycophenolate and tacrolimus. Three weeks after hospital discharge, however, the patient returned to the emergency department in respiratory distress with an O2 saturation of 84% on room air and a hemoglobin of 7.9 g/dl. Platelet and white blood cell counts were 88,000/ml and 3370/ml, respectively. Once again, BAL and chest CT were consistent with DAH and a thorough workup ruled out other etiologies for DAH. The patient was treated with a longer course of both

methylprednisolone (500 mg IV daily for five days) and plasma exchange (for 14 days), and she also received 100 g IVIG. Given the refractory nature of her DAH, there was a discussion on whether to initiate rituximab versus cyclophosphamide. Because the patient was pancytopenic and was already on immunosuppressive medications for her renal transplant, there was concern that further myelosuppression with a cytotoxic agent could worsen her clinical status. As a result, the patient received rituximab 550 mg (375 mg/m2) weekly  3 prior to discharge. She received the fourth and final dose of rituximab seven days after discharge. On initiation of rituximab treatment, the patient’s hemoglobin began to trend upward from a baseline of 7.9 g/dl to 10.3 g/dl (Figure 1). A repeat CT confirmed interval improvement in her ground-glass opacities, and she was discharged approximately five weeks after initial admission symptom free on a prednisone taper. She is now six months post-hospital discharge and free of DAH relapse.

Discussion Pulmonary complications in SLE are very common, occurring in up to 70% of patients. Such complications include pleuritis (most common), lupus pneumonitis, pulmonary embolism, infections, vasculitis, and, as in our case, diffuse alveolar hemorrhage. DAH represents among the most life-threatening of these complications, with recorded mortality rates of 50% or higher. Although there are fewer than 200 cases of

Figure 1 Hemoglobin trend in relation to rituximab dosing. Lupus

Downloaded from at University of Manitoba Libraries on June 9, 2015

Emerging treatment for recurrent diffuse alveolar hemorrhage in SLE JR Tse et al.


SLE-associated DAH published in the literature, estimates suggest that roughly 2% of SLE patients suffer from DAH.1 Therefore, DAH in SLE patients is much more common than the relative paucity of published case reports would suggest, and its significant mortality rate necessitates that further attention be paid to this disease. One potential trigger for our patient’s DAH may have been the withdrawal of hydroxychloroquine after her kidney transplant. In one randomized, double-blind, placebo-controlled study by the Canadian Hydroxychloroquine Study Group, discontinuation of hydroxychloroquine in the placebo group increased the risk of a clinical flare-up by 2.5 times when compared with continuing hydoxychloroquine.2 Moreover, the relative risk of a severe disease exacerbation requiring study withdrawal was 6.1 times higher in the placebo group. The time to a clinical flare-up was also shorter in the placebo group, and this difference was noticeable as early as two weeks after hydroxychloquine discontinuation.2 Table 1

Case reports examining rituximab in DAH-associated SLE

Patient identification

Clinical setting


24-year-old female Gillis et al., 2007 Arthritis Rheum5

Recurrent DAH; refractory to standard therapies


29-year-old female Nellessen et al., 2008 Nephrol Dial Transplant6 19-year-old female Pinto et al., 2009 Respiration7

Recurrent DAH; refractory to standard therapies


24-year-old female Todd and Costenbader, 2009 Lupus1

Recurrent DAH; refractory to standard therapies


52-year-old female Narshi et al., 2010 Rheumatology3

Used as early therapy with cyclophosphamide


18-year-old female Pottier et al., 2011 Lupus4

Intolerance to cyclophosphamide


32-year-old male Scheiman Elazary et al., 2012 Lupus8


23-year-old female Gonzalez-Echavarri et al., 2014 Lupus9

Recurrent DAH (15 attacks over 18 mos); antiphospholipid antibody; refractory to standard therapies DAH and acute pancreatitis; treated without high doses of prednisone


Pulse-dose steroids have long been used for the treatment of DAH. Over the past few decades, cyclophosphamide and plasma exchange have been added to this regimen; thus classical therapy for DAH in SLE patients currently includes highdose steroids, cyclophosphamide, and plasma exchange. Despite the additions of cyclophosphamide and plasma exchange, however, survival rates have shown only minimal improvement: one study showed a change in survival rate from only 48% to 53% with these changes.1 Further, given the significant adverse effects of cyclophosphamide and highdose steroids, these agents should be used only if their benefit can be convincingly established. Traditionally, cyclophosphamide is used as part of the first-line treatment regimen for DAH, and rituximab is considered only if there is no rapid improvement or if relapse occurs (see Table 1). However, previous cases have demonstrated successful clinical response when rituximab is initiated early in the hospital course prior to cyclophosphamide use3 or when rituximab is used alone because

Recurrent DAH; refractory to standard therapies

Treatments prior to rituximab IV cyclophosphamide, plasmapheresis, IVIG, pulsedose methylprednisolone, prednisone, succinate sodium, azathioprine (doses and days not documented), rituximab 375 mg/m2/week (four doses) AZA continued IV methylprednisolone 500 mg, cyclophosphamide 500 mg  2 18 days apart, rituximab 375 mg/m2/ week (2 doses) IV methylprednisolone 1 g/d  5 d, IV cyclophosphamide 1 g/d  5 d, IV rituximab 375 mg/m2 Relapse 1 week later: IV Methylprednisolone 1 g/d  5 d, IV cyclophosphamide 1 g/d  1 d, IV rituximab 375 mg/m2 IV methylprednisolone 1 g/d  3 d, then 1 mg/kg/d, cyclophosphamide 500 mg days 2, 17, 32, plasmaphoresis every other day  7 days, rituximab 375 mg/m2/2 weeks (six doses) IV methylprednisolone 1 g/d  3 d, then rituximab 1 g at day 9 and 25, IV cyclophosphamide day 10

IV methylprednisolone 1 g/d  3 d, then 1 mg/kg/d, 2 g/d mycophenolatemofetil  3 d, rituximab 375 mg/m2days 6 and 21 Prednisone 40–60 mg/d  6 mo, azathioprine 2 mg/kg  6 mo, IVIG 2 g/kg  3 mo, IV cyclophosphamide/mo  6 mo (7.5 g CYC cumulatively), rituximab 1 g/2 weeks  2 IV methylprednisolone 125 mg/d  1 d, then 250 mg/d  2 d, then 20 mg/d  1; cyclophosphamide 500 mg/d  1 d, prednisone taper

Outcome Decrease in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) at month 4. Relapse free at one year No episodes of DAH, f/u time not known Relapse free at six months

Deceased four months after discharge to home; cause of death unknown Resolution of cytopenias within one week; sustained decrease in dsDNA after one month f/u Relapse free at 15 months

Relapse free at 6 months, reports of rare and mild hemoptysis

Relapse free at 12 months

DAH: diffuse alveolar hemorrhage; SLE: systemic lupus erythematosus; IV: intravenous; IVIG: intravenous immunoglobulin; AZA: azathioprine; CYC: cyclophosphamide; dsDNA: double-stranded DNA; f/u: follow-up; mo: months; d: days. Lupus Downloaded from at University of Manitoba Libraries on June 9, 2015

Emerging treatment for recurrent diffuse alveolar hemorrhage in SLE JR Tse et al.

759 4

of cyclophosphamide intolerance. The promising results of these cases, in addition to cyclophosphamide’s potential toxicity to our patient given her pancytopenia, drove us to use rituximab instead of cyclophosphamide. Importantly, the combination of pulse-dose steroids, cyclophosphamide, and plasma exchange nonspecifically targets both the B- and T-cell branches of the immune system. Recent research in SLE pathophysiology, however, suggests that B-cell activation may be the main culprit in this disease process.5 This may be especially true in SLE-associated DAH, as microscopic images of lung biopsies from SLE patients with DAH show immune complex deposition along alveolar and blood vessel walls.6 Rituximab is a chimeric anti-CD20 monoclonal antibody used in the treatment of refractory autoimmune diseases. As CD20 is expressed by all B-cells, rituximab reduces cytokine secretion and autoantibody production by specifically targeting these B-cells.7 Although several randomized controlled trials examining the use of rituximab in SLE patients have reported heterogeneous results, preliminary reports examining the results of rituximab use specifically in SLE-associated DAH suggest uniformly promising outcomes (Table 1). In our patient, rituximab proved to be of remarkable benefit in both treating and preventing further relapse of DAH. Her hemoglobin improved and stabilized on initiation of rituximab treatment (Figure 1), and she did not require any additional or subsequent immunosuppressive agents. To the best of our knowledge, this represents the first reported case of SLE-associated DAH in a renal transplant patient. Given that renal disease is a common comorbidity in patients with SLEassociated DAH, the population of SLE-induced renal transplant patients suffering from DAH may be more common than the literature suggests. In addition, our patient was already on potent immunomodulatory drugs (methylprednisolone, thymoglobulin, and tacrolimus) at the time of development of her first episode of DAH. Given that thymoglobulin and tacrolimus specifically target the T-cell-mediated arm of the immune system, our patient’s DAH may provide further evidence that the B-cell-mediated branch of the immune system is most pathophysiologically relevant in the development of SLE-associated DAH. Furthermore, our patient achieved successful remission with rituximab without receiving cyclophosphamide. Although past case reports have similarly shown the benefit of rituximab in

SLE-associated DAH, all but one of these reports delivered rituximab in combination with cyclophosphamide.4 Therefore, our report further suggests that cyclophosphamide may not be essential to the treatment of SLE-associated DAH. Although further studies are needed prior to establishing practice guidelines, our case report highlights the importance of B-cell-mediated immunosuppression in the treatment of SLE-associated DAH.

Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.

Conflict of interest statement The authors have no conflicts of interest to declare.

References 1 Todd DJ, Costenbader KH. Dyspnoea in a young woman with active systemic lupus erythematosus. Lupus 2009; 18: 777–784. 2 The Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med 1991; 324: 150–154. 3 Narshi CB, Haider S, Ford CM, Isenberg DA, Giles IP. Rituximab as early therapy for pulmonary haemorrhage in systemic lupus erythematosus. Rheumatology 2010; 49: 392–394. 4 Pottier V, Pierrot M, Subra JF, et al. Successful rituximab therapy in a lupus patient with diffuse alveolar haemorrhage. Lupus 2011; 20: 656–659. 5 Gillis JZ, Dall’era M, Gross A, Yazdany J, Davis J. Six refractory lupus patients treated with rituximab: A case series. Arthritis Rheum 2007; 57: 538–542. 6 Nellessen CM, Po¨ge U, Brensing KA, Sauerbruch T, Klehr HU, Rabe C. Diffuse alveolar haemorrhage in a systemic lupus erythematosus patient successfully treated with rituximab: A case report. Nephrol Dial Transplant 2008; 23: 385–386. 7 Pinto LF, Candia L, Garcia P, et al. Effective treatment of refractory pulmonary hemorrhage with monoclonal anti-CD20 antibody (rituximab). Respiration 2009; 78: 106–109. 8 Scheiman Elazary A, Klahr PP, Hershko AY, Dranitzki Z, Rubinow A, Naparstek Y. Rituximab induces resolution of recurrent diffuse alveolar hemorrhage in a patient with primary antiphospholipid antibody syndrome. Lupus 2012; 21: 438–440. 9 Gonzalez-Echavarri C, Pernas B, Ugarte A, Ruiz-Irastorza G. Severe multiorganic flare of systemic lupus erythematosus successfully treated with rituximab and cyclophosphamide avoiding high doses of prednisone. Lupus 2014; 23: 323–326. 10 Garcı´ a-Carrasco M, Jime´nez-Herna´ndez M, Esca´rcega RO, et al. Use of rituximab in patients with systemic lupus erythematosus: An update. Autoimmun Rev 2009; 8: 343–348. 11 Green RJ, Ruoss SJ, Kraft SA, Duncan SR, Berry GJ, Raffin TA. Pulmonary capillaritis and alveolar hemorrhage. Update on diagnosis and management. Chest 1996; 110: 1305–1316. 12 Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA. Rituximab in systemic lupus erythematosus: A systematic review of off-label use in 188 cases. Lupus 2009; 18: 767–776.

Lupus Downloaded from at University of Manitoba Libraries on June 9, 2015

Rituximab: an emerging treatment for recurrent diffuse alveolar hemorrhage in systemic lupus erythematosus.

Diffuse alveolar hemorrhage (DAH) is a rare manifestation of systemic lupus erythematosus (SLE) and is associated with high mortality rates. Treatment...
92KB Sizes 0 Downloads 14 Views