Treatment of pulmonary hemorrhage in childhood systemic lupus erythematosus with mycophenolate mofetil. (Case Report).

Abstract: Systemic lupus erythematosus is a chronic autoimmune disease of unknown etiology with multisystem involvement. Pulmonary hemorrhage is a major life-threatening manifestation in children and adolescents with systemic lupus erythematosus, as well as in adults. Treatment has traditionally been with high-dose corticosteroids, with or without the addition of cytotoxic agents. We report the response of a patient with childhood systemic lupus erythematosus with recurrent pulmonary hemorrhage to treatment with mycophenolate mofetil.

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Discussion

Alveolar hemorrhage is bleeding from the small vessels of the pulmonary circulation. It is one of many causes of hemoptysis, which can also be caused by infections, neoplasms, foreign bodies, trauma, cardiac disease, or pulmonary vasculitis. In rheumatic diseases, pulmonary hemorrhage can be the primary manifestation of Goodpasture's syndrome, systemic vasculitides, or SLE. It can be secondary to drug ingestion, uremia, congestive heart failure, infection, embolism, or coagulopathy. (1-6) Travis et al (7) described 34 cases of diffuse pulmonary hemorrhage, reporting 43% of the cases caused by vasculitis, 13% caused by anti-basement membrane antibodies, 13% caused by idiopathic pulmonary hemosiderosis, 18% caused by pulmonary renal syndrome, and 13% caused by SLE or rheumatoid arthritis. The clinical presentation of a patient with pulmonary hemorrhage is usually hemoptysis and anemia, associated with diffuse or focal patchy alveolar infiltrates on chest x-ray. Pulmonary hemorrhage in SLE patients has been asso ciated with a high mortality rate, ranging from 70 to 95%, (1) and even if the patient survives, it can be recurrent.

Our patient presented with a flare-up of his SLE, manifested by leukopenia, anemia, seizure disorder, pulmonary hemorrhage, and renal insufficiency. His disease did not respond adequately to standard therapy for severe lupus nephritis, which includes treatment with TV steroids and pulse cyclophosphamide. Plasmapheresis and IVIG treatment did not lead to significant clinical improvement. In an attempt to control his diffuse pulmonary vasculitis, therapy with mycophenolate mofetil was begun.

There have been multiple recent reports of treating adult patients with rheumatic diseases with mycophenolate mofetil. (8-10) It is an immunosuppressive agent with the active metabolite mycophenolic acid, that inhibits proliferative responses of T and B lymphocytes and suppresses antibody formation by B lymphocytes. (8) It has a reversible antiproliferative effect without hepatotoxicity, nephrotoxicity, or mutagenicity. Mycophenolate mofetil has been used in adults to treat lupus nephritis, (9-12) psoriasis, (13) rheumatoid arthritis, (13) and inflammatory eye disease (14) and in patients receiving organ allografts. (15) There are no previous reports of its use to treat pulmonary hemorrhage in the pediatric population.

We report the improvement and control of active, severe lupus and one of its life-threatening complications, pulmonary hemorrhage, with mycophenolate mofetil therapy. After 15 days of treatment with mycophenolate mofetil, clearing was seen on the chest x-ray film, and a steady rise in serum complement values and a decline in anti-dsDNA antibody levels (Fig. 1) were seen by Day 21. Although improvement was seen in the serologic values after 3 weeks, the CH50 values did not normalize for 3 months (Fig. 1). This response time is consistent with those reported in other studies. (9,10,12-14)

Mycophenolate mofetil is an additional potential resource to the armamentarium in the treatment of severe SLE and its complications. It should be considered as an option in selecting long-term immunosuppressive therapy for patients with SLE, especially those who cannot tolerate cyclophosphamide therapy or whose condition failed to improve while taking cyclophosphamide.

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Accepted March 18, 2002.

References

(1.) Dweik RA, Arroliga AC, Cash JM. Alveolar hemorrhage in patients with rheumatic diseases. Rheum Dis Clin North Am 1997;2:395-410.

(2.) Ramirez RE, Glasier C, Kirks D, Shackelford GD, Locey M. Pulmonary hemorrhage associated with systemic lupus erythematosus in children. Radiology 1984;152:409-412.

(3.) Zamora M, Warner ML, Tuderand R, Schwarz MI. Diffuse alveolar hemorrhage and systemic lupus ezythematosus: Clinical presentation, histology, survival, and outcome. Medicine (Baltimore) 1997;76:192-202.

(4.) Schwab EP, Schumacher HR Jr, Freundlich B, Callegari PE. Pulmonary alveolar hemorrhage in systemic lupus erythematosus. Semin Arthritis Rheum 1993;23:8-15.

(5.) Feiliu M, Lee JH, Weng TH, Lee YY. Clinical experience of 13 cases with severe pulmonary hemorrhage in systemic lupus erythematosus with active nephritis. Scand J Rheumatol 1998;27:291-295.

(6.) Miller RW, Salcedo JR, Fink RJ, Murphy TM, Magilavy DB. Pulmonary hemorrhage in pediatric patients with systemic lupus erythematosus. J Pediatr 1986;108:576-579.

(7.) Travis WD, Colby TV, Lombard C, Carpenter HA. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol 1990;14:1112-1125.

(8.) Hoffman RL, Reeder SJ. Mycophenolate mofetil (Cellcept): The newest immunosuppression. Crit Care Nurse 1998;18:50-57.

(9.) Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993;135:5-25.

(10.) Glicklich D, Acharya A. Mycophenolate mofetil therapy for lupus nephritis refractory to intravenous cyclophosphamide. Am J Kidney Dis 1998;32:318-322.

(11.) Balow JE, Austin HA III, Tsokos GC, Antonovych TT, Steinberg AD, Klippel JH. NIH conference: Lupus nephritis. Ann Intern Med 1987;106:79-94.

(12.) Dooley MA, Cosio FG, Nachman PH, Falkenhain ME, Hogan SL, Falk RJ, et al. Mycophenolate mofetil therapy in lupus nephritis: Clinical observations. J Am Soc Nephrol 1999;l0:833-539.

(13.) Epinette WW, Parker CM, Jones EL, Greist MC. Mycophenolic acid for psoriasis: A review of pharmacology, long-term efficacy, and safety. J Am Aced Dermatol 1987;17:962-971.

(14.) Larkin G, Lightman S. Mycophenolate mofetil: A useful immunosuppressive in inflammatory eye disease. Ophthalmology 1999;106:370-374.

(15.) Ulsh PJ, Yang HC, Holman MJ, Ahsan N. New strategies using "low-dose" mycophenolate mofetil to reduce acute rejection in patients following kidney transplantation. J Transpl Coord 1999;9:114-118.

RELATED ARTICLE: Key Points

* Pulmonary hemorrhage is a life-threatening manifestation of systemic lupus erythematosus.

* Factors contributing to pulmonary hemorrhage include acute immune complex disease, infection, and bleeding diathesis.

* Patients can develop pulmonary hemorrhage even while receiving high doses of steroids for treatment of active systemic lupus erythematosus.

* Mycophenolate mofetil is a potentially useful drug in the management of systemic lupus erythematosus and its complications.

Case Report

A 14-year-old Hispanic boy who had been diagnosed in Mexico with lupus nephritis 2 years before was admitted to a local community hospital with complaints of fatigue, abdominal pain, and arthritis. He had run out of his medication (prednisone) several weeks before the onset of symptoms.

Laboratory values at admission to that facility were as follows: white blood cell count, 2.2 X [10.sup.3]/[micro]l; hemoglobin, 7.7 mg/dl; hematocrit, 23%; platelet count, 319 x [10.sup.3][micro]l; blood urea nitrogen, 64 mg/dl; creatinine 2.0 mg/dl; and antinuclear antibody ratio, 1:1,280. Urinalysis was abnormal, with hemoglobinuria (3+) and proteinuria (3+). Treatment with prednisone was begun (60 mg orally, four times per day). The patient developed extensive hemoptysis and hypoxemia, and was intubated for ventilatory support. Chest x-ray film revealed bilateral interstitial infiltrates, cardiomegaly, and right pleural effusion. Bronchoscopy confirmed pulmonary hemorrhage. The patient was given IV pulse methylprednisolone and 1 g of IV cyclophosphamide. His condition stabilized, and he was extubated. Computed tomographic scan of the head showed several ischemic areas consistent with old infarction, as well as possible acute cerebritis. He experienced a second episode of pulmonary hemorrhage and a grand ma l seizure, and was transferred to the University of Kansas Medical Center.

At admission to our facility, his blood pressure was 144/97 mm Hg, his pulse was 83 beats/mm, his respiratory rate was 20 breaths/mm, and his temperature was 370C. On examination, he had a malar rash, bilateral basilar rales, moderate ascites, and pedal edema, but no pleural rub, murmur, or organomegaly. Neurologic examination was normal. Laboratory values were as follows: white blood cell count, 1.2 x [10.sup.3]/[micro]l; hemoglobin, 9.0 mg/dl; hematocrit, 26.4%; platelet count, 248 X [10.sup.3]/[micro]l; total hemolytic complement, 14 U (normal, 57-147 U); blood urea nitrogen, 59 mg/dl; creatinine, 1.6 mg/dl; erythrocyte sedimentation rate, 11 mm/h; C-reactive protein, 1.3 mg/dl; anti-dsDNA antibody, 714 IU (normal, <40 IU); immunoglobulin G (IgG), 418 mg/dl; immunoglobulin M (IgM), 29 mg/dl; and immunoglobulin A (IgA), 63 mg/dl. Tests for anti-Smith and anti-ribonucleoprotein antibodies were positive, as was the test for perinuclear antineutrophilic cytoplasmic antibody. Tests for cytoplasmic antineutrophi lic cytoplasmic antibody and anti-glomerular basement membrane antibody were negative. Levels of the third and fourth components of complement (C3 and C4) were 18.9 mg/dl (normal, 88-200 mg/dl) and <10 mg/dl (normal, 16-47 mg/dl), respectively.

Chest x-ray showed bilateral diffuse alveolar infiltrates. Computed tomographic scan of the chest showed extensive bilateral nodular alveolar infiltrates, bilateral pleural effusions, and mild cardiomegaly.

The patient received 1 g IV pulse methylprednisolone daily for 3 days, and received treatment on alternate days with plasmapheresis (X4) and IV immunoglobulin (IVIG; 500 mg/kg/d). Ten days after admission, he had his first episode of hemoptysis (approximately 150 ml) since being transferred to our facility. He was intubated again and continued receiving treatment with IV methylprednisolone (60 mg every 12 h). His blood and urine cultures were negative for microorganisms. Therapy was begun with IV mycophenolate mofetil (500 mg, twice per day) and total parenteral nutrition, and he continued receiving mechanical ventilation. Serologic studies were repeated 8 days later and showed the following values: C3, 76.0 mg/dl; C4, 36.4 mg/dl; total hemolytic complement (CH50), 101 U/ml; IgG, 1,940 mg/dl; anti-dsDNA, 10 IU; and creatinine, 1.7 mg/dl. Kidney biopsy revealed membranoproliferative glomerulonephritis with focal crescent formation, chronic and active, consistent with class IV lupus nephritis. The patient's ren al function deteriorated further, with blood urea nitrogen level of 67 mg/dl and creatinine level of 2.9 mg/dl, and hemodialysis was begun. On day 15 of treatment with mycophenolate mofetil (500 mg IV, twice per day), hydroxychloroquine (200 mg, twice per day), and methylprednisolone (40 mg IV, bid), serologic studies were repeated and revealed a total complement level of 117 U and an anti-dsDNA level of 21 IU; urinalysis showed no blood, no protein, and a creatinine level of 2.4 mg/24 h. He was extubated on Day 23 of treatment with mycophenolate mofetil. He continued to take mycophenolate mofetil (500 mg orally, twice per day), hydroxychloroquine (200 mg, twice per day), and prednisone (10 mg/d) until discharge, and also underwent twice weekly hemodialysis.

From the Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas.

Reprint requests to Carol B. Lindsley, MD, Department of Pediatrics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Room 2026, Kansas City, KS 66160-7330. Email: [e-mail]

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