Bone Marrow Transplantation (2001) 27, 337–340 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt
Case report Successful treatment of thrombocytopenia and hemolytic anemia with IvIG in a patient with lupus-like syndrome after mismatched related PBSCT A Hartert, W Willenbacher, S Gu¨nzelmann, E Roemer, N Basara, AA Fauser and MG Kiehl Clinic of Bone Marrow Transplantation and Haematology/Oncology, Idar-Oberstein Germany
Summary:
Hematopoietic stem cell transplantation (HSCT) can cause clinical symptoms characteristic of autoimmune diseases like myasthenia gravis, immune thyroiditis, as well as immune cytopenia.1–11 Especially, autoimmune cytopenia is mostly refractory to standard therapeutic approaches.2,3 We herein report a patient with a lupus-like syndrome associated with hemolytic anemia and severe thrombocytopenia after HSCT.
weakness, edema, anemia, thrombocytopenia, and erosive cutaneous lesions. He had received a conditioning regimen consisting of busulfan (4 mg/kg bw × day on days −7 to −4) and cyclophosphamide (60 mg/kg bw × day on day −3 and day −2) before PBSCT. The donor was the patient’s sister. The patient’s blood group was A Rh positive, CMVIgG seropositive and HLA-typing demonstrated HLAA01/01, B 8/35, Cw 040/0701, DR 12/11, DRB1 120/110, and DQB1 0301/0603. He received peripheral blood stem cells form his A Rh positive, CMV seronegative and HLA partially mismatched (DRB1 010×/110×; DQB1: 0501/0603) sister. The graft contained 2.28 × 106 CD34+ cells/kg/bw. GvHD prophylaxis consisted of cyclosporine (CYA) starting on day −3, prednisolone starting on day +7 after transplantation and MTX given as a short course on days +1, +3 and +6 at a dose of 15 mg/m2 and twice at 10 mg/m2, respectively. Engraftment (leukocyte count ⬎1000 × 109/l, neutrophil count ⬎0.5 × 109/l) occurred on day +21 after PBSCT. He developed slight cutaneous GVHD grade I–II which responded promptly to increased immunosuppression with prednisolone (0.7 mg/kg bw × day) for 1 week, then tapered, and mycophenolate-mofetil (MMF) (2 g/day) for 3 months. CMV reactivation, as diagnosed by CMV-PCR, occurred 2 months after PBSCT (recipient CMV IgG positive, donor CMV IgG negative). This was successfully treated with ganciclovir, but the PCR became positive again shortly after cessation of therapy. He therefore received cidofovir as maintenance for 2 months. Immunosuppressive therapy on admission consisted of prednisolone 5 mg/day and CYA 150 mg/day given orally (blood level 284 ng/ml).
Patient characteristics
Clinical findings
Hematopoietic stem cell transplantation (HSCT) is a treatment option for autoimmune diseases but can also cause clinical features similar to those of autoimmune diseases. In some of these cases the autoimmune-like condition is associated with autoimmune cytopenia, a complication that can be unresponsive to established treatment strategies and which may be fatal. The majority of cases reported on immune hemolytic anemia have been of alloimmune origin due to ABO red blood cell antigen incompatibilities between donor and recipient. We now report a patient with a lupus-like syndrome, presenting with severe thrombocytopenia and hemolytic anemia 9 months after HLA-mismatch, ABO compatible-related PBSCT who experienced no response to high-dose steroids, but who had a sustained response to repeated IvIG therapy. Bone Marrow Transplantation (2001) 27, 337–340. Keywords: autoimmune cytopenia; hematopoietic stem cell transplantation; lupus-like syndrome; alloimmunity; IvIG
Nine months (day +277) after a mismatched related allogeneic stem cell transplant (PBSCT) for CML in first CP, a 38-year-old patient presented with weight gain, general Correspondence: Dr MG Kiehl, Clinic of Bone Marrow Transplantation and Oncology/Oncology, Dr Ottmar-Kohler-Str. 2, 55743 IdarOberstein, Germany Received 31 May 2000; accepted 4 October 2000
As papular cutaneous lesions were the main clinical finding a viral infection was suspected, possibly herpes virus or VZV reactivation. CMV testing had been negative for the last 4 months. However, the CMV-PCR was positive at the time of admission. He was treated with foscarnet to avoid further myelosuppression in a graft which was already suboptimal. Testing for VZV and HSV was negative. Within a few days of admission the patient developed
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fever, arthralgia, severe pancytopenia, generalized edema, polyserositis with pericardial and pleural effusions, and nephrotic syndrome. Creatinine levels increased to 176.8 mol/l and creatinine clearance decreased to 83 ml/min, with a mixed glomerular/tubular proteinuria of 4.5 g/l. He had oliguria with a further weight gain of nearly 7 kg, and for 1 week he experienced diarrhea which commenced shortly after the onset of these symptoms. A bone marrow biopsy showed mild hypoplasia, incompatible with the severe peripheral cytopenia. Folic acid, vitamin B12 and iron levels were within normal ranges; the ferritin level was increased to 774 ng/ml. The hemoglobin decreased to 40 g/l, leukocyte count to 1.5 × 109/l from 3.1 × 109/l, and platelet count to 6 × 109/l from 66 × 109/l (Figure 1). The reticulocyte count was 4.2%. Coagulation parameters were within the normal ranges. Endoscopy revealed no gastrointestinal bleeding, but GVHD grade 2 of the bowel was diagnosed histologically. The pancytopenia was refractory to platelet and red cell transfusion. We observed a slight increase in bilirubin levels to 27.36 mol/l, but hapoglobins remained within the normal range (53 mg/dl). Blood smears showed fragmented cells indicating severe haemolysis and the direct Coombs test was positive. Further analysis revealed polyspecific antibodies and ANA titers which increased from 1:20 000 to 1:40 000 within 3 weeks with homogenous a IF-pattern, and concomitant slightly elevated anti ds-DNA antibodies (25 U/l and 30 U/l). Anti Scl 70, Ro/SS-A, c-ANCA, p-ANCA, MPO, C3 nephritis factor, anti-tubular and anti-glomerular basal membrane antibodies were negative. C3 complement was decreased to 68 mg/dl (normal range 90–180 mg/dl) and C4 complement factor was reduced to levels below 11 mg/dl (10–40 mg/dl). Lupus-anticoagulant was negative. Clinical course and therapy On admission (day +277 after PBSCT) skin rash, diarrhea three to four times a day, and pancytopenia were observed and interpreted as GVHD of the skin and bowel, associated with graft dysfunction, possibly CMV associated. Joint pains were interpreted as symptoms of CMV disease. PCR testing was positive, but pp65 Ag was negative. Administration of foscarnet, twice a day (90 mg/kg) improved the clinical symptoms of CMV disease and the cytopenia
Platelet counts
140
Platelets (x109/l)
120
resolved slowly. Colonoscopy demonstrated discrete changes compatible with intestinal GVHD grade I. Thus, the prednisolone dose was increased from 5 mg/day to 12.5 mg/day, whereas the other immunosuppressive medication remained unchanged for the first days of inpatient treatment. Intestinal symptoms improved within 1 week. A few days after admission the patient developed a temperature up to 38.8°C. No infection focus was found. Testing for other herpes viruses including VZV and EBV was negative. With the onset of fever the hemoglobin and platelet levels dropped to 4 g/dl and 6000/l, respectively, without increment after transfusion. Direct Coombs testing was positive and blood smears showed fragmented cells due to hemolysis. The edema worsened with a further increase in body weight up to 96.2 kg. Ultrasound and CT scan revealed a polyserositis. CYA medication for GVHD prophylaxis was immediately stopped and replaced by MMF because of a possible CYA-induced microangiopathy. Autoantibody screening was performed and findings corresponded to an autoreactive process after allogeneic PBSCT, comparable to a lupus-like syndrome that met six of the ARC criteria for SLE (serositis, arthralgia, ANA, Anti-ds-DNA, Coombs positive anemia, thrombocytopenia, proteinuria, discoid skin lesions). We did not perform a kidney biopsy to assess the grade of renal involvement because of the refractory thrombocytopenia. Neither patient nor donor had a history of rheumatic disease. No other relative had suffered from autoimmune disease. Treatment consisted of prednisolone 75 mg for 8 days, then reduced to 50 mg/day, and MMF 2 g/day. Intravenous immunoglobulin (IvIG) treatment was started at a dose of 0.4 mg/kg bw on 5 consecutive days. A total of four cycles was given. Oliguria and edema were treated with furosemide and xipermide. Renal function subsequently improved markedly. On day +329, 2 months after symptom onset, the serum creatinine was within the normal range and proteinuria decreased from 4.5 g/l to 0.8 g/l. The patient’s body weight declined from 96 kg (maximum) to his regular body weight of 72 kg and he no longer required diuretics. Hemoglobin level (50 g/l) and platelet count (23 × 109/l) were still low at the time of discharge on day +368 and there were no clinical signs of anemia or bleeding. Hb and platelets increased during the following 2 weeks to levels of 70 g/l and 50 × 109/l, respectively. Three weeks later (day +398) the patient was readmitted with new self-limiting
IvIG
100 80 60 40 20 0
270 275 279 283 291 297 305 335 341 370 400 421 447 533
Days post HSCT Figure 1 Response of platelet counts to IvIG treatment. ↓, IvIG treatment. Bone Marrow Transplantation
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Successful treatment of thrombocytopenia after PBSCT with IvIG A Hartert et al
episodes of arthralgia, decrease in platelet count (39 × 109/l) and Hb (37 g/l) associated with a slight reduction (35 to 30 mg/day) in steroid therapy. Serum-PCR testing for CMV was again positive. There was no renal involvement. The patient received a course of foscarnet for 5 days, followed by ganciclovir p.o. for 4 weeks at a dose of 3 g/day. IvIG was given at a dose of 0.4 mg/kg bw for 5 days and resulted in a marked increase in the platelet count to 84 × 109/l. Hb increased slowly to 51 g/l at discharge after IvIG therapy. IvIG was repeated 2 weeks later at a reduced dose of 5 g/day for 5 days, repeated 4 weeks later. The Hb was stable above 90 g/l and the platelet count remained above 40 × 109/l from approximately day +400. ANA titers were still high at 1:20 000–40 000, anti-dsDNA dropped to levels below 8 U/ml. CMV testing was negative from October 1999. IvIG was given every 4 weeks from October 1999. The patient has been very well meanwhile and there have been no similar episodes since August 1999. The platelet count has been ⬎80 × 109/l since November 1999, Hb has remained ⬎90 g/l. There are no signs of GVHD. Day +769 blood counts are Hb 141 g/l, platelets 144 × 109/l, leukocytes 4.5 × 109/l. GVHD prophylaxis/ immunosuppressive therapy consists of 3 mg prednisolone/day and MMF 750 mg/day. Discussion Autoimmune-like conditions such as immune thyroiditis, cytopenia, myasthenia gravis, and polymyositis have been reported after allogeneic, syngeneic and even autologous hematopoietic stem cell transplantation (SCT).4–10 Cytopenia after allogeneic SCT is a common phenomenon and can occur secondary to various immune or non-immune mechanisms. In this case a non-immune mechanism such as graft failure, peripheral consumption due to bleeding, sepsis or relapse of the underlying disease could be excluded. As demonstrated by Sherer and Shoenfeld1 the prevalence of autoantibodies in long-term survivors of allogeneic SCT is increased. These autoantibodies are not necessarily associated with clinical symptoms.1 Chronic GVHD occurs in 25–70% of patients after allogeneic SCT and can cause symptoms resembling autoimmune-disease such as Sjo¨gren’s syndrome, scleroderma, and autoimmune hepatitis. However, it is unclear how GVHD can be distinguished from these clinical syndromes. Possibly such diseases depend on an underlying autoimmune disease in the donor or recipient.9 In our case neither patient nor donor had a history of autoimmune symptoms and therefore the revelation of a pre-existing autoimmune syndrome or transfer of an autoimmune disease seems unlikely. Immune cytopenia post-allogeneic SCT may be explained by recipient-versus-donor (HVG) reactions as a result of alloantibodies of host origin, or otherwise donor-versus-donor reactions due to loss of autoregulative T cells and consecutive loss of tolerance against autoantigens. These effects may contribute to autoimmunelike syndromes. Infections are another important cause of allo or autoimmune phenomena induced by antigenic crossreactivity. It should be noted that our patient developed lupus-like symptoms during CMV reactivation, indicating infection as a possible trigger of these immune phenomena.
Various drugs can induce an SLE-like syndrome. One of these is cyclosporine. It has been reported to possibly cause a comparable autoimmune disease associated with microangiopathy, cytopenia, and positive ANA titers.11 However, detection of anti-ds DNA as was the case in our patient, is rare. As our patient had only one episode of hemolysis and acute thrombocytopenia after cessation of CYA therapy, a drug-related effect might have contributed to his lupus-like syndrome. In addition, it is unclear whether this syndrome is a real autoimmune phenomenon or a symptom of chronic GVHD. Previous case reports about cytopenia and especially severe thrombocytopenia after SCT have demonstrated that thrombocytopenia is associated with IgG or IgM platelet-specific antibodies.1,2 Therapy consisted of prednisolone given at a dose of 1– 2 mg/kg × day and/or high-dose IvIG and/or anti-D immunoglobulin, and even plasma exchange.1,2,10 In some cases complete recovery has been reported after IvIG. On the other hand, several of these cases proved to be therapy refractory and the clinical course was fatal.2,3 The causes of failure or success of therapeutic modalities in severe autoimmune cytopenia/ thrombocytopenia are still unknown. In our patient, no anti-platelet antibodies were detected, but we observed an auto-antibody pattern resembling SLE with a poor response to steroid therapy. Nevertheless, a sustained response to IvIG therapy was observed. Whether further escalation of the steroid dose (dexamethasone) would have led to the same result is an open question, but as our patient had CMV reactivation at the same time, more aggressive steroid therapy was avoided. In conclusion, use of high-dose IvIG is a good treatment option for patients with autoimmune thrombocytopenia after SCT.
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