Systematic Review of Diffuse Alveolar Hemorrhage in Systemic Lupus Erythematosus Focus on Outcome and Therapy

REVIEW

Christina Ednalino, MD, Julie Yip, DO, and Steven E. Carsons, MD

to be an adjuvant therapy in SLE patients not only for DAH, but Background: Diffuse alveolar hemorrhage (DAH) is an uncommon but other severe manifestations such as glomerulonephritis and potentially life-threatening manifestation of systemic lupus erythematosus neuropsychiatric SLE. Because of the rarity of DAH in SLE, pro- (SLE) associated with high mortality. Although survival and its associated spective studies are difficult to perform, and most of the published clinical, laboratory, and therapeutic features have been reported for case re- literature on this condition is in the form of case reports and case se- ports and series, they have not been systematically reviewed. ries. We have conducted a systematic review of 140 subjects with Objectives: The purpose of this systematic review was to assess survival DAH in SLE, to evaluate survival with adjunctive plasmapheresis. of episodes of DAH in SLE over 3 decades and to categorize trends in therapies, commonly utilized to treat this disorder. Results: Overall, SLE patients survived 61% of 174 DAH episodes METHODS representing 140 patients. Episode survival was 67% in the time period A PubMed search was performed using the terms [Alveolar from 2000 to 2013. Corticosteroids were nearly universally used therapeu- OR Pulmonary Hemorrhage] AND [Systemic Lupus Erythemato- tically, and cyclophosphamide was used in 55%. Plasmapheresis was used sus] for all publications between 1981 and February 2014. Case in 31% and did not appear to be associated with survival. reports and series where patients had a diagnosis of SLE in addi- Conclusions: Diffuse alveolar hemorrhage in SLE still carries a high tion to diffuse alveolar hemorrhage (DAH) were included. Exclu- risk of mortality; however, survival trends appear to demonstrate an in- sion criteria included age younger than 18 years, pregnancy, crease from approximately 25% in the 1980s to 67% in the current decade. antineutrophil cytoplasmic antibody (ANCA) positivity, and other Increased use of cyclophosphamide appears to be associated with better conditions known to cause pulmonary hemorrhage such as con- survival, whereas plasmapheresis does not appear to influence outcome. comitant antiphospholipid antibody syndrome, uremia, dissemi- Although these results need to be interpreted with caution because they nated intravascular coagulation, or cytomegalovirus pneumonia. are not derived from randomized controlled trials, we believe this repre- We also excluded articles in which individual survival data were sents the largest reported compilation of survival data in DAH associated not available. The 2 searches yielded 395 results. The search re- with SLE. sults were cross-referenced for duplicates. Abstracts were excluded if any of the exclusion criteria were apparent, or if the Key Words: diffuse alveolar hemorrhage, plasmapheresis, article was not in English. Fifty-nine full articles were reviewed systemic lupus erythematosus to ensure that inclusion and exclusion criteria were satisfied. A (J Clin Rheumatol 2015;21: 305–310) total of 44 articles were selected for final analysis. There were 24 single case articles and 20 multiple case articles. The largest iffuse alveolar hemorrhage (DAH) is an uncommon, poten- number of analyzed cases in a single article was 22, and only D tially life-threatening manifestation of systemic lupus erythe- 2 articles contained greater than 10 analyzed cases. Qualifying matosus (SLE), occurring in less than 2% of patients.1–4 Diffuse publications were reviewed, and data entered into a predesigned alveolar hemorrhage in SLE has historically been associated with electronic spreadsheet. Clinical manifestations, laboratory and ra- a high mortality; the majority of reported rates falling between diographic data, treatment, and survival outcome were analyzed 70% and 90%.1,4–6,9 The condition is typically characterized by for cases where such specific information was given. The utilization shortness of breath with or without hemoptysis, new infiltrates of plasmapheresis was examined by subject, as well as by episode in on chest radiography, and a drop of hemoglobin of at least the event multiple episodes of DAH occurred for a single subject. 1.5 g/dL. While the pathogenesis of DAH is still not well under- Selected treatment and outcome variables were further analyzed stood, reported histological findings include bland alveolar hemor- by decade. Association of survival with treatment was analyzed rhage without vasculitis, diffuse alveolar damage, and interstitial using Fisher exact test (Graphpad Software Inc., La Jolla, CA). inflammation.1,10,11 Current management for DAH in SLE includes high-dose intravenous corticosteroids, intravenous cyclophospha- RESULTS 12 mide, and extensive supportive care. Plasmapheresis (PF) has been Twenty-seven articles comprising 80 cases were published be- used in SLE patients since the early 1980s; however, the earliest 13 tween 2000 and 2013, 9 articles comprising 48 subjects were pub- studies failed to confirm their benefit. Nevertheless, PF continues lished between 1990 and 1999, and 8 articles with 19 total subjects were from 1980 to 1989. Publication dates did not always corre- ’ From the Division of Rheumatology, Allergy & Immunology, Winthrop- spond with the decade in which a patient s episode occurred. There University Hospital, Clinical Campus of Stony Brook University School were 140 patients with 174 episodes of DAH among them. Ages of Medicine, Mineola, New York. ranged from 18 to 72 years. Eighty-five percent were female. S.E.C. has consulted with Biogen-Idec. The other authors declare no conflict of interest. Correspondence: Steven E. Carsons, MD, Division of Rheumatology, Allergy & Clinical Manifestations Of SLE In Patients With DAH Immunology, Winthrop-University Hospital, 120 Mineola Blvd, Suite 410, In patients for whom individual data were available, clini- Mineola, NY 11501. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. cal manifestations were analyzed (Table 1). Forty-four percent ISSN: 1076-1608 had joint involvement, 60% had mucocutaneous symptoms, and DOI: 10.1097/RHU.0000000000000291 25% had neuropsychiatric involvement. Seventy-three percent

JCR: Journal of Clinical Rheumatology • Volume 21, Number 6, September 2015 www.jclinrheum.com 305

Association Of Survival With Therapeutic TABLE 1. Patient Characteristics of the 140 Cases Reviewed Modalities Age (range), y 18–72 Overall, patients survived 107 (61%) of 174 episodes; 73 Female-male ratio 85:15 (52%) of 140 cases survived. Of those who received plasmapheresis, 23 (53%) of 43 survived (Table 3). In the cases where PF was Nephritis 73% not used, survival was 50 (51%) of 97. When analyzed by epi- Other renal 9% sodes, 65% (35/54) were survived with plasmapheresis. If PF Cytopenias 71% was not used, episode survival was 60% (72/120) (not statistically Mucocutaneous 25% significant). Seventy (71%) of 98 episodes where cyclophospha- Articular 44% mide was used resulted in survival. Patients survived 37 (49%) Dyspnea on presentation 90% of 76 episodes where cyclophosphamide was not used. (relative Hemoptysis 57% risk, 0.68; P = 0.0028). In patients receiving cyclophosphamide, Elevated dsDNA antibody 75% data on pheresis use were available for 71 episodes; pheresis was Low complement 86% used in 24 (33.8%). For patients not receiving cyclophosphamide, data on pheresis use were available for 68 episodes; pheresis was used in 13 (19.1%). Thus, pheresis was used more often in patients who were treated with cyclophosphamide. had prior or active glomerulonephritis, and an additional 9% had renal abnormalities ranging from elevated creatinine or urinary protein, abnormal urinary sediment, or unspecified kidney in- Infection And Outcomes volvement. Upon presentation 89 (90%) of 92 had dyspnea, and The cause of death was provided for 36 cases. Forty-four 71 (57%) of 124 patients had hemoptysis. One hundred two epi- percent were from pulmonary hemorrhage alone, 28% were sodes presenting with hemoptysis had outcome data reported. listed as either cardiopulmonary or pulmonary failure. In 8 Sixty episodes presented with hemoptysis, and 39 (65%) sur- (22%), infection was listed as a cause of death. In 5 cases, in- vived. Forty-two episodes presented without hemoptysis and 26 fection was primary (1 each: pneumonia, left lower lobe pneu- (62%) survived. monia, Acinetobacter sepsis, pneumocystis pneumonia, and Pseudomonas sepsis), and in 3, it was contributory (hemorrhagic pneumonitis with bronchopneumonia, Legionella sepsis Laboratory Data And Clinical Outcome with pulmonary hemorrhage, and pulmonary hemorrhage Seventy (61%) of 114 had cytopenias, 62 (75%) of 83 had with infection). elevated double-stranded DNA, and 84 (86%) of 98 had hypo- The use of antibiotics was reported for 82 episodes. Antibi- complementemia. Despite the high prevalence of hypocomplemen- otics were used in 60; 41 survived (68%). Antibiotics were not temia overall, the normocomplementemic patients (24 episodes) used in 22; 14 survived (64%). had a lower survival (8 episodes; 33%) as compared with the hypocomplementemic patients (99 episodes), where 81 episodes were survived (82%) (odds ratio, 9; P < 0.001). Outcome And Pheresis Use By Decade Cases reported from 1980 to 1989 had an overall episode survival rate of 25%. Survival was 64% from 1990 to 1999 and 68% Diagnosis And Treatment Of DAH In SLE from 2000 to 2013. In the 1980 reports, no subjects received pheresis, whereas the percentage of patients receiving pheresis from Data from chest imaging were available for 132 cases. Dif- 1990 to 1999 was 38% and 33% from 2000 to 2013. In the fuse alveolar or interstitial infiltrates were seen in 107, patchy in- 1990 cases, 61% of those pheresed survived and 66% of those filtrates in 15, lobar infiltrates in 6, and ground-glass patterns in 3. not pheresed survived. For the cases reported from 2000 to Pleural effusion accompanied the above patterns in 10. In 1 case, 2013, 68% receiving pheresis survived, and 68% of those not normal findings were reported. In this patient, the diagnosis of pheresed survived. DAH was made clinically based on hemoptysis, dyspnea, and No reported cases were treated with CYC in the 1980s. Cy- a drop in hemoglobin. Bronchoalveolar lavage was performed clophosphamide (CYC) was used in 54% of episodes from on 53 patients. Hemorrhage or bloody return was seen in 35, 1990 to 1999 and 70% from 2000 to 2013. In the 1990s, 64% hemosiderin-laden macrophages in 8, and a positive result for of patients survived regardless of whether they received CYC. infection was seen in 4 patients (2 pneumocystis pneumonia, 1 cy- From 2000 to 2013, 72% of patients treated with CYC survived, tomegalovirus, and 1 Legionella bozemanii). One sample was whereas 50% of patients not receiving CYC survived. positive for both hemorrhage and infection. Lung biopsy data were available for 49 patients. Features consistent with pulmonary hemorrhage (capillaritis, blood, hemosiderin-laden macrophages) were observed in 33; hemorrhage plus inflammation was found in TABLE 2. Therapeutic Agents Utilized to Treat DAH 7; inflammatory cellular infiltrates alone were seen in 2; hemorrhage plus infection in 1, electron-dense deposits in 1, and no ev- Corticosteroids 98% idence of hemorrhage in 5 patients. Treatment was variable Cyclophosphamide 54% among patients (Table 2). Corticosteroids were used in 144 Plasmapheresis 31% (98%) of 147 episodes. Plasmapheresis was utilized in 31% Azathioprine 7% of both cases and episodes. Seventy-six (54%) of 140 patients Intravenous immunoglobulin 5% received or had been receiving cyclophosphamide. Other ther- Mycophenolate 3% γ apies included azathioprine (7.4%), intravenous -globulin Rituximab 6% (4.6%), mycophenolate (2.9%), and stem cell transplantation Stem cell transplantation 2% (2.3%). Eight patients (5.7%) received rituximab; 5 survived.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. C:Junlo lnclRheumatology Clinical of Journal JCR: 05WlesKue elh n.Alrgt reserved. rights All Inc. Health, Kluwer Wolters 2015 © TABLE 3. Outcome in Diffuse Alveolar Hemorrhage in SLE

Pheresis Subjects Pheresis Episodes CTX Subjects CTX Episodes WithPF WithoutPF WithPF WithoutPF WithCTX WithoutCTX WithCTX WithoutCTX First Author Year of Study Survived Died Survived Died Survived Died Survived Died Survived Died Survived Died Survived Died Survived Died Hoshi14 2003 1 000100000100010 Todd15 2009 1 000100010001000 Al Rashidi12 2011 1 000100010001000 Santos16 2004 0 001000100010001 17

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Sengul 2011 0 010001010001000 • Pottier18 2011 1 000100000100010 oue2,Nme ,Spebr2015 September 6, Number 21, Volume Pinto4 2009 0 010001010001000 Ichikawa19 1989 0 010002000100020 Sarma20 1985 0 001000100010001 Someren21 1983 0 001000100010001 Tandon22 2000 1 000100000100010 Yan o 23 1992 0 010001000100010 Sureda24 1990 1 000100010001000 Takei2 2007 0 010001010001000 Huang25 1996 0 001000100010001 Porres-Aguilar26 2008 0 100011001001100 Tojo27 1989 0 001000100010001 Narshi28 2010 0 010001010001000 Martinez-Martinez29 2012 0 010004010004000 Claridge30 2011 1 000100010001000 Carvalheira31 2010 0 010001010001000 Liang32 2010 0 010001010001000 Desnoyers11 1984 0 010001000100010 Virdi33 2012 0 010001010001000 Erickson34 1994 2 100810021008100 Cañas35 2007 1 120114031005100 Santos-Ocampo36 2010 x xxx5060xxxx8030 www.jclinrheum.com Badsha37 2003 6 58365831361213612 1 Zamora 1997 1 553245427412751 SLE in Hemorrhage Alveolar Koh38 1997 1 242124252025202 Lee9 2000 3 201320120132013 Chang39 2002 0 023002311121112 Hughson3 2001 0 002001202001200 Lee40 2001 0 034005421132133 Schwab8 1993 1 051107140215031 307 Continued next page Ednalino et al JCR: Journal of Clinical Rheumatology • Volume 21, Number 6, September 2015

DISCUSSION Diffuse alveolar hemorrhage is a severe complication of SLE with reported mortality rates up to 50%.1 Despite the life- threatening nature of this disorder, treatment is largely empiric. We undertook this systematic review in order to explore trends in presentation, survival, and therapy. In particular, the roles of apheresis and cyclophosphamide in the management of DAH in SLE were examined. Corticosteroids were used nearly universally in the treatment of DAH in SLE; therefore, it is impossible to draw conclusions related to corticosteroids and survival. It is reasonable to use high- dose corticosteroid until hemorrhage ceases. Cyclophosphamide was used in approximately one-half and apheresis in approximately one-third. Pheresis is utilized in the therapy of other disorders presenting with pulmonary hemorrhage including ANCA-associated vasculitis,46 cryoglobulinemic vasculitis,47 and anti–glomerular basement membrane (anti-GBM) disease.48 It is thought that re- moval of circulating immune complexes, ANCA, and anti-GBM antibodies ameliorates pulmonary capillaritis. Because 82% of cases had renal involvement, there are likely to be similar mech- anisms responsible for immune-mediated capillary damage in lupus glomerulonephritis and in alveolar hemorrhage. Of 6 instances where immunofluorescence results on lung tissue were reported, 5 were positive for immunoglobulin and/or complement depo- sition. The data reported here suggest that pheresis does not influence survival in DAH associated with SLE. Perhaps dsDNA antibodies, which were present in approximately 75% of cases reviewed, are not directly pathogenic in alveolar hemorrhage in SLE or that these antibodies are already bound to the alveolar capillary membrane at presentation. Nonetheless, an overwhelming number of DAH-SLE patients were hypocomplementemic, consistent with an immune complex–mediated etiology. Paradoxically, hypocomplementemia was inversely associated with survival in the cases reviewed. Perhaps, low complement values at presentation prompted earlier, more aggressive treatment. Nevertheless, it would be appropriate to utilize pheresis at least until anti- GBM disease is excluded. In contrast to pheresis, the use of CYC appeared to be associated with improved survival (71% vs 49%). Survival appears to have increased incrementally by decade from the 1980s until present. This is likely in great part due to advances in the care of the critically ill patient and in the treatment of opportunistic and 09000900090009 25006502230263 12001200120012 11001100110011 10011000110011 03000303000300 03000301020102 20122000320032 30003020102010 iatrogenic infections. While the use of phresis has risen from 0% in the 1980s to 68% in the years following 2000, it does not seem to have had an effect on survival. In contrast, use of CYC seems to be associated with increased survival during the latter period

Pheresis Subjects Pheresis Episodes CTX Subjectswhere CTX Episodes survival was 49% in the patients not treated with CYC and 71% in the CYC-treated patients. It is important to note that WithPF WithoutPF WithPF WithoutPF WithCTX WithoutCTX WithCTX WithoutCTX

23 20 50these 47 associations 35 19 are 72 estimates 48 derived 48 from 28 compiled 25 retrospec- 39 70 28 37 39 tive reports and do not represent statistical trend analyses. The most recent series on DAH in SLE was published by Martinez-Martinez et al.49 They retrospectively reviewed 57 episodes that included adult as well as pediatric cases (aged <18

1985199819801984 02009 02009 02013 0 01991 0 02011 0 0 0 0 1 1 0 0 0 2 0 years). The prevalence of major clinical and laboratory characteristics was similar to those summarized here in Table 1 and included renal disease in 79%, hypocomplementemia in 68%, and hemoptysis in 58%. Their survival (58%) mirrored the overall sur-

6 43 vival reported here (approximately 61% of episodes), although individual survival data were not provided. The authors emphasized (Continued) 42

7 that the mortality rate was highest in those receiving mechanical 44 5 10 ventilation, renal failure, infection, high Acute Physiology and 41 45 Chronic Health Evaluation II scores, and thrombocytopenia. In TABLE 3. isAto YearofStudySurvivedDiedSurvivedDiedSurvivedDiedSurvivedDiedSurvivedDiedSurvivedDiedSurvivedDiedSurvivedDied FirstAuthor Abud Mendoza Liu Marino Carette Kobayashi Abud Mendoza Sharma Onomura Shi the data reviewed here, infection contributed to mortality in

22%. While it could not be determined if antibiotic use contributed 13. Pagnoux C. Plasma exchange for systemic lupus erythematosus. Transfus to survival, improved antibiotic selection, dosing, and prompt initi- Apher Sci. 2007;36:187–193. ation of antimicrobial therapy may help increase survival rates. In 14. Hoshi K, Matsuda M, Ishikawa M, et al. Successful treatment of fulminant DAH, chest imaging usually reveals diffuse alveolar infiltrates but pulmonary hemorrhage associated with systemic lupus erythematosus. pleomorphic patterns may be observed; if the patient’scondition Clin Rheumatol. 2004;23:252–255. permits, bronchoalveolar lavage and biopsy appear useful to ex- 15. Todd DJ, Costenbader KH. Dyspnoea in a young woman with active clude infection and other autoimmune lung pathology. This rein- systemic lupus erythematosus. Lupus. 2009;18:777–784. forces the concept that improvements in survival in large part 16. Santos BH, Santos RR, Santos CF, et al. 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Recurrent lupus pneumonitis controlled study examining the effect of the addition of pheresis with pulmonary hemorrhage in systemic lupus erythematosus associated to steroids and CYC would be necessary to definitively determine with chronic thyroiditis and antithyroid hormone autoantibodies. Clin Exp Rheumatol. 1989;7:309–313. the role of pheresis in therapy for DAH in the context of SLE. In addition, rituximab may be a promising approach to the treatment 20. Sarma PS, Viswanathan KA, Mukherjee MM, et al. Fatal pulmonary of DAH in SLE. Infection was the cause or contributed to mortal- haemorrhage in systemic lupus erythematosus. J Assoc Physicians India. – ity in approximately one-quarter of episodes. A high suspicion for 1985;33:796 797 799, 801. concomitant infection coupled with prompt, well-targeted antibi- 21. Someren AO, Honig E, Gaffney E, et al. 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