Sj�gren's Syndrome Complicated with Thrombotic Thrombocytopenic Purpura: A Case Report and Literature Review  

Yida Xing , Xiaodan Kong , Hongjiang Wang , Yan Zhang
Department of Rheumatology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
Author    Correspondence author
International Journal of Clinical Case Reports, 2013, Vol. 3, No. 14   doi: 10.5376/ijccr.2013.03.0014
Received: 29 Aug., 2013    Accepted: 30 Aug., 2013    Published: 30 Aug., 2013
© 2013 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

The association of Sjögren's syndrome (SS) with thrombotic thrombocytopenic purpura (TTP) is rare, but it carries a high death rate and can be easily misdiagnosed. We report a case of TTP with SS and the related literature is reviewed. A previously healthy 72-year-old woman presented with an acute onset of marked thrombocytopenia and then dizziness, fatigue, fever and fainting. Schirmer's test was bilaterally positive, associated with positive Rose Bengal corneal staining. Radionuclide imaging of the glands showed abnormalities. The presence of anti-SSA and anti-SSB antibodies confirmed the diagnosis of SS. The patient was treated successfully with plasma exchange therapy, plasma infusion, glucocorticoid, and immunosuppressive agents. Her condition has remained stable after 6 months of follow-up. Only a few cases of SS complicated with TTP have been described in the literature. Rheumatologists should pay attention to this special condition because it is rare and has a high mortality rate.

Keywords
Sjögren's syndrome; Thrombotic thrombocytopenic purpura; Autoimmune

1 Introduction
Sjögren’s syndrome (SS) is a common autoimmune disease (AID) characterized by exocrine gland damage, and mainly affects the salivary glands and lacrimal gland. Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening condition with significant mortality and is associated with many diseases. The association of SS with TTP is rare, but it carries a high death rate and can be easily misdiagnosed (Kremer Hovinga et al., 2010). We report herein a case of SS complicated with TTP. Furthermore, we review 14 similar cases reported in the literature and briefly discuss the manifestations of this special condition. 

2 Case Presentation
A 72-year-old woman with fatigue for 5 days and purpura on her limbs for 2 days came to our clinic. She also had gingival bleeding, bloody sputum, and bloody urine for 2 days. When she came to us on November 1, 2011, her blood tests showed: white blood cell (WBC) count 4.91×109/L, hemoglobin (Hb) 80 g/L, platelet (PLT) count 4.4×109/L; fasting blood glucose 4.7 g/L; urine tests showed occult blood (3+). She was admitted to our hematology department on November 3, 2011. She had no relevant medical, family or drug history. Physical examination revealed ochrodermia and purpura on her limbs. Her nervous system examination was normal. Her WBC count had decreased to 2.81×109/L, Hb decreased to 82 g/L, and PLT count reduced to 3×109/L. Her purpura had gotten worse and she was given a platelet transfusion on the first day after hospitalization. Her laboratory tests were: AST 54 IU/L, ALT 37 IU/L, LDH 862 IU/L, TB 23.4 mol/L, DB 7.2 mol/L, CRP 1.9 mg/dL, BUN 56.7 mg/dL, IgG 15.7 g/L, IgA 4.97 g/L, IgM 0.61 g/L, IgE 449 g/L, antinuclear antibody 1: 3 200 (granular pattern) positive, anti-SSA antibody positive, anti-SSB antibody positive. Renal function test, anti-dsDNA antibody and anti-phospholipid antibody were all negative, and serum levels of C3, C4 were in the normal range. The patient was ANCA negative and chest X-ray was normal. Bone marrow smear was unremarkable. The patient had had mild dry mouth and dry eyes for 10 years. A diagnosis of connective tissue disease (CTD) was made and the patient was transferred to our rheumatology and immunology department. On the first night in the in-patient ward, the patient presented with sudden speech disorder and allolalia. She also had a fever (peaking at 38.1?) with no symptoms or signs of infection. The nervous system examination was unremarkable. A cranial computed tomography revealed mild white matter demyelination. She was treated with oxiracetam, but her speech and allolalia got worse, and, in addition, she was restless and became comatose. A repeated brain nuclear magnetic resonance showed a new ischemic focus on the right parietal lobe and on both sides of the frontal lobe. Her PLT count and Hb level were 60×109/L and 6.6 g/L, respectively. Bone marrow biopsy disclosed a hypoproliferative marrow with normal maturation of granulocytic series. Coombs’ test was negative. D-dimer, prothrombin time (PT), and activated partial thromboplastin time (APTT) were all within normal limits. Twenty-four hour urine protein secretion was 676 mg. She was diagnosed with TTP. She was immediately given a plasma exchange once daily for 6 days (2 000 mL on each occasion), then the frequency was changed to every other day (2 000 mL on each occasion), and, at the same time, high-dose methylprednisolone was infused (120 mg for 3 days, then 80 mg for 5 days, after which this was changed to prednisone 60 mg each day). Two days after the plasma exchange, her PLT count increased to 68.4×109/L. Furthermore, her LDH level decreased from 875 to 219 U/L. After her PLT count rose to 60×109/L, Schirmer’s test was bilaterally positive, associated with positive Rose Bengal corneal staining. Radionuclide imaging of the glands showed abnormalities. Ophthalmologic evaluation was consistent with keratoconjunctivitis sicca. Salivary gland biopsy revealed inflammatory infiltrations of lymphocytes in the periductal and periacinar areas. A diagnosis of primary SS (pSS) was made. Immunoglobulin injection was given for 5 days and mycophenolate mofetil was added at the same time. After this treatment, the patient’s condition improved remarkably. She remains stable and continues to be followed-up at our out-patient clinic. She now takes prednisone 10 mg qd and mycophenolate mofetil 1.0 bid. Eight months later, her laboratory studies were: WBC count 9.76×109/L, Hb 147 g/L, PLT count 214×109/L, serum AST 27 IU/L, ALT 22 IU/L, LDH 126 IU/L, IgG 10.7 g/L, IgA 3.42 g/L, IgM 1.01 g/L, IgE 71 g/L. 

3 Discussion
SS is a common AID characterized by an exocrine gland disorder in which the salivary and lacrimal glands are most commonly involved. Hematological manifestations of pSS usually consist of mild anemia and thrombocytopenia, and moderate neutropenia and lymphopenia. Hematological changes include purpura haemorrhagica, anemia, immune-induced hemolytic anemia, eosinophilia, leukemia, aplastic anemia, and lymphoma. Laboratory examination may show multiclonal hyperglobulinemia, high titer rheumatoid factor, and an evident increase in the erythrocyte sedimentation rate. Individual cases of TTP preceding the diagnosis of SS, systemic lupus erythematosus (SLE) or scleroderma have been reported. A close relationship between SLE and TTP was first described in 1939. TTP is frequently associated with CTD, with a frequency of 1%~6% in the patient population (Sato et al., 2006); however, TTP associated with SS is rare. TTP is a pathological condition characterized by generalized microvascular occlusion by platelet thrombi, thrombocytopenia, and microangiopathic hemolytic anemia. It is a syndrome consisting of hemolytic anemia, thrombocytopenic purpura, neurologic disease, fever, and renal disease. It was ?rst described by Moschcowitz in 1925. In contrast to idiopathic TTP, the causes associated with TTP include drugs (especially chemotherapeutic agents), malignancy, CTDs, hematopoietic stem cell transplantation, Escherichia coli O157 H7, pregnancy, and many other causes (Yoshihiro and Masanori, 2010). Endothelial cell injury is the postulated mechanism of TTP. Endothelial dysfunction, including release of nitric oxide and von Willebrand factor, and increased levels of tissue plasminogen activator, thrombomodulin, plasminogen activator inhibitor, are described as promoting the development of TTP (Yoshihiro and Masanori, 2010). ADAMTS13 is synthesized in endothelial cells and megakaryocytes from identical 250 kD subunits into disul?de-linked multimers ranging in size from about 500 to 20 000 kD (Gerritsen et al., 2001). It was initially identified within the liver, and then more specifically in hepatic stellate cells (Uemura et al., 2005). ADAMTS13 is also present in platelets (Suzuki et al., 2004), vascular endothelial cells (Manea et al., 2007), and kidney podocytes (Manea et al., 2007). Severe deficiency of ADAM TS-13 activity (ADAMTS13:AC) has been thought to be a unique feature of TTP, and can be caused by genetic mutations or by acquired autoantibody (ADAMTS13:INH) to this enzyme (Furlan et al., 1998; Tsai and Lian, 1998). ADAMTS13 is assumed to efficiently cleave unusually large VWF multimers (UL-VWFMs) released from vascular endothelial cells as a solid phase enzyme by binding to the cell surface, after secretion into the circulation (Coppo and Veyradier, 2009). Although TTP is a highly heterogeneous pathological condition, one-third of TTP patients have severe deficiency of ADAMTS13:AC. Platelet transfusions in such patients are contraindicated.

Plasma exchange is now the most common first-line therapy for TTP. In addition to corticosteroids, immunosuppressive agents and immunoglobulin are needed for CTD-associated TTP. The possible mechanism of plasma exchange is removal of the noxious substance in the patient’s circulation blood, such as autoantibody, and it can also supply certain agents, such as blood coagulation factor. High-dose corticosteroids and immunosuppressive agents can inhibit immune inflammatory reaction and the activity of T/B cells in order to decrease cytokinemia and autoantibody, and are considered to be beneficial in maintaining a good long-term prognosis in immuneinduced TTP. The effect of large-dose immunoglobu-
lin and immunosuppressive agents has not been confirmed yet, but in our case, large-dose immunoglobulin and immunosuppressive agents did prove to be effective. 

A review of the literature revealed 14 other such cases (Table 1): 14 out of 15 patients were female, 3 patients died after plasma exchange and glucocorticosteroid treatment, and 2 patients died quickly after diagnosis but before treatment. Relapsing and chronic forms of TTP are unusual. In one case, ADAMTS13 activity was negative. Plasma exchange, plasma infusion, and glucocorticosteroid were used as therapy. In one case, rituximab (375 mg/m2) was used as the disease-modifying antirheumatic drug (DMARD). For our patient, the DMARD used was mycophenolate. After treatment, the patient’s condition stabilized, and to date, the patient continues to be healthy with no disease recurrence.
 


Table 1 Comparison of reported patients with SS complicated with TTP


Since SS complicated with TTP is a rare but life-threatening condition with a high death rate, and misdiagnosis is high, more attention should be paid to it in clinical practice.

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