Mod Rheumatol (2012) 22:280–283 DOI 10.1007/s10165-011-0489-5
CASE REPORT
Mycophenolate mofetil therapy for juvenile dermatomyositis with immune thrombocytopenic purpura Chikara Ogimi • Nazuna Honma • Risa Tanaka Tsutomu Oh-ishi
•
Received: 14 October 2010 / Accepted: 2 June 2011 / Published online: 28 June 2011 Ó Japan College of Rheumatology 2011
Abstract A 6-year-old girl, who had received corticosteroid and cyclosporine on the diagnosis of interstitial pneumonitis related to juvenile dermatomyositis, developed severe thrombocytopenia. Her thrombocytopenia was resistant to repeated intravenous immunoglobulin administration and methylprednisolone pulse therapy. After additional treatment with mycophenolate mofetil (MMF), instead of cyclosporine, the thrombocytopenia improved, facilitating a reduction in the dose of corticosteroid without exacerbation of the interstitial pneumonitis. We propose MMF as effective option in the treatment of immune thrombocytopenic purpura with autoimmune disease. Keywords Cyclosporine Immune thrombocytopenic purpura Interstitial pneumonitis Juvenile dermatomyositis Mycophenolate mofetil
Introduction Autoimmune diseases such as systemic lupus erythematosus are frequently associated with thrombocytopenic purpura, and this is occasionally referred to as immune thrombocytopenic purpura (ITP) [1, 2]. However, few reports are available on ITP associated with juvenile dermatomyositis (JDM) [3]. Of note, mycophenolate mofetil (MMF) has been used widely to treat patients with systemic lupus erythematosus, including a few with concomitant ITP [4–6]; however, there is no report about the use of this agent in JDM with concomitant ITP. We report here a case of a girl with JDM who developed ITP, which was successfully treated with MMF.
Case report Abbreviations ITP Immune thrombocytopenic purpura JDM Juvenile dermatomyositis MMF Mycophenolate mofetil PAIgG Platelet-associated IgG
C. Ogimi N. Honma R. Tanaka T. Oh-ishi Division of Infectious Disease, Immunology, and Allergy, Saitama Children’s Medical Center, Saitama, Japan Present Address: C. Ogimi (&) Division of Infectious Diseases, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan e-mail:
[email protected]
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A 6-year-old girl was admitted with petechiae. Sixteen months before this admission, she had been diagnosed with JDM because she had Gottron’s sign, erythema on the extensor aspect of the extremities, weakness of the proximal muscles of the upper and lower limbs, elevated muscle enzymes (creatine phosphokinase [CPK] 36 IU/l, aldolase 11.3 U/l, and urine myoglobin 15.1 ng/ml), arthritis without bone and cartilage destruction, an elevated erythrocyte sedimentation rate, positive anti-Jo-1 antibody (anti-histidyl tRNA synthetase antibody), and muscle biopsy and electromyographic findings compatible with dermatomyositis. She had no family history of autoimmune disease, and her platelet count was normal (330 9 103/ll). She was positive for antinuclear antibodies (speckled pattern, 25609) and her KL6 level was elevated, at 689 U/ml, without respiratory symptoms. She received methylprednisolone pulse therapy followed by prednisolone at
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1 mg/kg/day (15 mg/day), and showed rapid improvement. Her disease condition was stable after the initial therapy, and she recovered her full strength on manual muscle testing. Eight months before the present admission, her KL6 level had increased to 800 U/ml, and chest computed tomography (CT) showed a slight decrease in radiolucency when prednisolone was tapered to 6.5 mg/day. Interstitial pneumonitis associated with JDM was diagnosed, and cyclosporine (5 mg/kg/day) was administered in addition to prednisolone. On admission, her vital signs were normal (height 1.2 SD; weight 1.3 SD). Petechiae were observed on the palpebra and lower extremities, without Gottron’s sign or erythema. There were no abnormal findings related to her lung, heart, muscle, or joints, or to other autoimmune diseases such as vitiligo, psoriasis, or celiac disease. Her laboratory values on admission are listed in Table 1. She had severe thrombocytopenia without coagulation abnormalities. Retrospective review showed that her platelet count had been slightly decreased 1 month prior to admission (142 9 103/ll). She had no history of an antecedent event, such as upper respiratory infection or vaccination, in the few weeks before the occurrence of the thrombocytopenia. Increased titers of various autoantibodies, including platelet-associated immunoglobulin G (PAIgG), were observed. The bone marrow findings
Table 1 Laboratory findings
were unremarkable except for the proliferation of megakaryocytes. After admission (Fig. 1), she was diagnosed with ITP associated with JDM and intravenous immunoglobulin was administered at a dose of 1 g/kg for 2 days, without distinct improvement. On day 4 of hospitalization, she began a 3-day course of methylprednisolone pulse therapy (30 mg/kg/day), which resulted in a transient increase in the platelet count. Therefore, intravenous immunoglobulin was again administered, for 2 days, a second course of methylprednisolone pulse therapy was given, and the dose of prednisolone following the pulse therapy was increased to 2 mg/kg/day. Rapidly progressive anemia (hemoglobin 7.6 g/dl on day 17) developed because of profuse nasal bleeding that occurred despite these treatments; therefore, MMF therapy (500 mg/ day) and platelet transfusion were initiated on day 15 of hospitalization; erythrocyte transfusion and intravenous immunoglobulin were administered for 2 days on day 17 of hospitalization. When her platelet count decreased again on day 24 of hospitalization, a third course of methylprednisolone pulse therapy was administered. The PAIgG level normalized after MMF was initiated, and the thrombocytopenia improved. At present, since the prednisolone had been tapered to 4.5 mg/day for 25 months, there has been no exacerbation of thrombocytopenia or interstitial pneumonitis. She has not, to date, developed ectopic calcification.
Hematology
Immunology
WBC
8600/ll
IgG
1428 mg/dl
Hgb
13.6 g/dl
IgA
316 mg/dl
Platelets ESR
2000/ll 30 mm/h
IgM C3
295 mg/dl 106 mg/dl
C4
16 mg/dl
PT
11.8 s
CH50
30 U/ml
APTT
31.8 s
RF
1 IU/ml
Fibrinogen
293 mg/dl
Antinuclear antibody
6409
PAIgG
46.9 ng/107 cells (\25)
Anti-dsDNA antibody
Negative
Anti Jo-1 antibody
28.9 (\9)
Coagulation
Biochemistry Figures in parentheses are normal ranges WBC white blood cell count, Hgb hemoglobin, ESR erythrocyte sedimentation rate, PT prothrombin time, APTT activated partial thromboplastin time, RF rheumatoid factor, PAIgG platelet-associated immunoglobulin G, ds doublestranded, BUN blood urea nitrogen, LDH lactate dehydrogenase, CPK creatine phosphokinase, CRP C-reactive protein, CyA cyclosporine
Glucose
92 mg/dl
Lupus anticoagulant
Negative
BUN
13 mg/dl
Anticardiolipin IgG
Negative
Creatinine
0.26 mg/dl
Immune complex (C1q)
Negative
GOT
29 IU/l
GPT
13 IU/l
CyA serum concentration
101 ng/ml (trough)
LDH
318 IU/l
Direct Coombs test
Negative
CPK
41 IU/l
Indirect Coombs test
KL6 CRP
451 U/ml (\250) 0.10 mg/dl
Aldolase
10.4 U/l (\7.5)
Myoglobin serum
3.8 ng/ml
Myoglobin urine
10.5 ng/ml (\10)
Other parameters
Bleeding time Urinalysis
Negative 6 min 30 s Normal
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282 Fig. 1 Clinical course during hospitalization. Changes in bleeding symptoms, platelets, and platelet-associated IgG during treatment. Day 1 denotes first day of hospitalization. Pulse denotes methylprednisolone pulse therapy. PSL prednisolone, IVIG intravenous immunoglobulin, PAIgG platelet-associated IgG
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Nasal bleeding Pulse Pulse Cyclosporine
PSL 2mg/kg/day
Pulse Mycophenolate mofetil
IVIG Erythrocyte transfusion Platelet transfusion
Platelets (/ml)
PAIgG Platelets PAIgG
400,000 300,000
(ng/107cells)
75
50
200,000 25 100,000 0
1
10
Discussion We have reported here a case of a girl with JDM who developed ITP, which was later successfully treated with MMF. To our knowledge, few reports are available on ITP associated with JDM [3]. Kobayashi et al. [3] reported children with JDM who developed severe thrombocytopenia with a decrease in megakaryocyte numbers. Kobayashi et al. [3] regarded macrophage activation as the main mechanism of the thrombocytopenia, which was successfully treated with cyclosporine, corticosteroid, and intravenous immunoglobulin. However, in our patient, an antiplatelet antibody was regarded as the main mechanism of thrombocytopenia, because during the treatment with cyclosporine, refractory thrombocytopenia developed with high PAIgG levels and without laboratory findings suggestive of macrophage-activating syndrome. The standard treatment for ITP associated with systemic lupus erythematosus involves the use of steroids, and if that is ineffective, various therapies, using intravenous immunoglobulin, immunosuppressants, rituximab, splenectomy, and plasma exchange have been attempted [1, 7]. A few reports are available on the use of MMF in the treatment of ITP associated with systemic lupus erythematosus [5]; however, there are no reports of its use in JDM and adult dermatomyositis. In our patient, the platelet count increased within 2 weeks of MMF initiation, a finding in agreement with previous reports, although therapy with intravenous immunoglobulin and methylprednisolone was also administered. Of note, Kotb et al. [8] found that MMF was effective in 7 of 9 patients with refractory idiopathic thrombocytopenic purpura unassociated with autoimmune
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20 30 Days after admission
40
50
0
disease and in all 5 patients with autoantibodies. Furthermore, Zhang et al. [9] noted that MMF was effective in 16 of 20 patients with refractory idiopathic thrombocytopenic purpura, and IgG, IgA, IgM, and PAIgG levels decreased in 86% of the patients after MMF initiation. In our patient, immunoglobulin and PAIgG levels were also reduced after MMF was initiated. These results indicate that MMF is effective for the treatment of thrombocytopenic purpura, whether or not it is associated with autoimmune diseases. In our patient, anti-Jo-1 antibody was positive when interstitial pneumonitis developed. Anti-Jo-1 antibody is strongly correlated with intestinal pneumonitis [10, 11]. When ITP developed in our patient, MMF was initiated instead of cyclosporine, which has been used to treat interstitial pneumonitis related to JDM. We note that our patient’s KL6 level is currently stabilized at \400 U/ml despite steroid tapering. KL-6 is a human glycoprotein secreted by type II alveolar cells in the lung, and it has been correlated with interstitial lung impairment [12, 13]. Although there are a few reports showing that MMF administration resulted in pulmonary fibrosis in patients with renal transplantation [14, 15], other studies have reported the effectiveness of MMF in the treatment of interstitial pneumonitis associated with autoimmune diseases, including adult polymyositis/dermatomyositis [16, 17]. The proposed mechanisms of the effective action of MMF include the inhibition of not only the proliferation of lymphocytes but also the proliferation and activation of fibrosis-related fibroblasts, smooth muscle cells, and endothelial cells [16, 18]. Immunosuppressive agents such as methotrexate or cyclophosphamide have been used to treat refractory JDM
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[19]; however, the use of these drugs was limited in our patient because of potential adverse effects such as interstitial pneumonitis and gonadal toxicity. MMF has recently been used widely in the treatment of autoimmune diseases, mainly lupus nephritis, with relatively few serious adverse effects. Some studies have also suggested its effectiveness for the muscle weakness and cutaneous symptoms of adult polymyositis/dermatomyositis [20–22], as well as its effectiveness in JDM [23]. In our department, we are currently treating 4 JDM patients, including the present one, with MMF. They are all showing favorable clinical responses to the treatment. However, a randomized controlled study is needed to verify the efficacy of MMF in JDM. In summary, our patient was a girl with interstitial JDMrelated pneumonitis who developed ITP. The ITP was resistant to high-dose corticosteroid and intravenous immunoglobulin therapy, but the thrombocytopenia improved after MMF initiation. We propose that MMF may be effective for the control of JDM, and for the treatment of ITP associated with autoimmune diseases. Conflict of interest
None.
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