The coexistence of autoimmune rheumatic diseases and thymomas

Background. Autoimmune rheumatic diseases (ARDs), involving immune disturbances resulting from auto-inflammatory mechanisms, are a group of diseases characterized by autoimmunity and autoimmune-mediated organ damage. Thymoma, whose mechanism is also associated with immune abnormalities, is the most common neoplasm of the anterior mediastinum. But thymoma with ARDs is relatively less frequent. The clinical characteristics of the coexistence of ARDs and thymomas are still not very clear. And the therapeutic strategy for ARDs combined with thymomas varies, with an uncertain outcome. Objectives. The aim of this study was to investigate the clinical characteristics of the coexistence of ARDs and thymomas in order to speculate whether a thymectomy is effective for ARDs combined with thymo-mas, and to seek the proper therapeutic strategy for treating ARDs combined with thymomas. Material and methods. We presented 2 cases of the coexistence of ARDs and thymomas. Then, we summarized 20 cases (including our 2 cases) in which the ARD was diagnosed concurrently with, or prior to, the thymoma. Results. Pure red cell aplastic anemia (PRCA) might be associated with an ARD and a thymoma, and a thy-mectomy may lead to the appearance, exacerbation, or remission of ARDs. Conclusions. Searching for a thymoma is necessitated if a patient with ARDs experiences PRCA and the effects of thymectomy in ARDs combined with thymomas may be associated with the onset sequence of ARDs and thymomas.

Autoimmune rheumatic diseases (ARDs) are a group of rare, heterogeneous disorders characterized by autoimmunity and autoimmune-mediated organ damage.They affect an estimated 7.6-9.4% of the population worldwide, and they include systemic lupus erythematosus (SLE), Sjögren's syndrome (pSS), rheumatoid arthritis (RA), dermatomyositis (DM), and systemic sclerosis (SSc), etc. 1 Thymoma is the most common tumor in the anterior mediastinum. 2However, the combination of an ARD and a thymoma in the same patient is relatively less frequent.Herein, we will present 2 ARD cases that also simultaneously had a thymoma.

Case 1
A 60-year-old Chinese woman was diagnosed with SLE in 2005 at another hospital because she had polyarthritis, alopecia, neutropenia, and low complete C3/C4 levels, along with positive antinuclear antibody and anti--dsDNA antibody tests.She was 1 st treated with prednisone (50 mg/day), wilfordii (60 mg/day), and methotrexate (10 mg/week), and her maintenance treatment included prednisone (10 mg/day) for a long time while her disease was stable.She was admitted to our hospital in March 2014 because of dizziness, fatigue, and mild shortness of breath that had persisted for 3 months.A physical examination revealed a pale appearance and mild lower extremity edema.Laboratory findings were as follows: hemoglobin, 30 g/L; ANA, positive, (with a titer of 1 : 160; granular pattern); anti-dsDNA antibody, negative; anti-histone antibody and antiribosomal protein antibodies, positive; complement C3 and C4, 483.0 mg/L and 55.3 mg/L, respectively; and Coombs and Ham tests, negative.The albumin level was 30.9 g/L.A bone marrow cytology test performed in another hospital was as follows: active bone marrow hyperplasia; granulocyte prolifera- tion; and significantly reduced red blood cell hyperplasia.The megakaryocytes were normal and the platelets were distributed in clusters.The peripheral blood slides were normal.Pure red cell aplastic anemia (PRCA) was diagnosed.A chest computed tomography (CT) scan revealed a mass in the right anterior mediastinum that measured 68 mm × 62 mm (Fig. 1), with a right pleural effusion.A CT-guided percutaneous needle biopsy of the mass was performed on March 28.The pathological result showed a type B3 thymoma (Fig. 2), according to the World Health Organization (WHO) classification.A thymectomy was not performed because she had severe anemia.She was treated as follows: methylprednisolone (40 mg/day), hydroxychloroquine (0.2 g/day), and regular blood transfusions.Hydroxychloroquine (0.2 g/day) and regular blood transfusions were continued, and for daily maintenance, methylprednisolone was gradually reduced to 12 mg.Upon her follow-up, her disease was deemed to be stable.

Case 2
A 63-year-old Chinese woman with a history of hypothyroidism was diagnosed with Sjögren's syndrome in 2007 at our hospital based on dry mouth, dry eyes, positive antinuclear antibody and anti-SSA/SSB tests, and positive corneal fluorescein staining, along with a tear film breakup time of 3 s.Anti-Sm antibody and anti-dsDNA antibody tests were both negative.A urinalysis was negative for proteinuria, and a chest radiograph was normal at that time.She was treated with methylprednisolone (40 mg/ day), wilfordii (60 mg/day), leflunomide (10 mg/day), and levothyroxine (100 μg/day) for her illness.This treatment protocol was continued, and for daily maintenance, methylprednisolone was gradually reduced to 4 mg.The disease was stable during follow-up.The patient was admitted to our hospital again because of lower limb edema on August 19, 2014.
Upon admission, a physical examination revealed 4 dental caries with a residual root only and lower extremity edema.The laboratory findings were as follows: blood cell counts, normal; proteinuria, 3+; 24-h urinary protein, 3.43 g; globulin, 51.60 g/L; albumin, 27.50 g/L; triglyceride, 1.58 mg/L; cholesterol, 6.27 mmoL/L; ANA titer, 1 : 320 (homogeneous pattern); anti-SSA and anti-SSB tests, positive; and anti-Sm antibody and anti-dsDNA antibody tests, negative.A chest CT revealed a large mass measuring 39 mm × 31 mm in the area of the thymus (Fig. 3).
A thymectomy was performed on August 26, 2014.A type B3 thymoma was considered according to the WHO classification, and the tumor did not involve any other structures (Fig. 4).More than 1 month after the thymectomy, the patient was admitted to our hospital again because of exacerbation of lower extremity edema; the laboratory values were as follows: Blood cell counts, normal; proteinuria, 3+; globulin, 28.60 g/L; albumin, 24.08 g/L; triglycerides, 1.58 mg/L; cholesterol, 7.70 mmoL/L; ANA titer, 1 : 320 (homogeneous pattern);

Discussion
ARDs are a group of diseases involving immune disturbances resulting from auto-inflammatory mechanisms that are frequently the underlying cause. 1 A thymoma is the most frequent tumor of the thymus, the mechanism of which is also associated with immune abnormalities. 2 Structural and functional changes in the thymus may lead to the loss of self-tolerance and may occur with autoim- mune diseases. 2There are 3 morphological types of thymomas based on genetic alterations according to 2004 WHO classifications: A, B (B1, B2, and B3), and AB.Carcinoma of the thymus is designated as type C. Compared with type A, B1, B2, and AB, the B3 subtype has high 15-year recurrence rates and a poor prognosis. 3A thymoma is commonly associated with a variety of systemic and autoimmune disorders such as PRCA, hypogammaglobulinemia, pancytopenia, collagen diseases, and most commonly, myasthenia gravis (MG); sometimes 2 or even 3 autoimmune diseases coexist. 4][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Several reports documented the appearance of ARD after a thymectomy for a thymoma.Other reports described the appearance of a thymoma years after a patient was diagnosed with an ARD, as in our 2 cases.In some cases, the 2 diagnoses were concurrent.Herein, we have summarized 20 cases (including our 2 cases) and have included relatively complete information.For all 20 cases, the ARD was diagnosed concurrently with or prior to the thymoma (Table 1).
The association of a thymoma with an ARD is not frequent.In clinical studies, the prevalence of SLE in patients with a thymoma varied between 1.5 and 2%. 16PRCA has been associated with a thymoma or ARD.Approximately 2-5% of patients with a thymoma will have PRCA. 21RCA could also arise as a complication of an ARD such as SLE, but it is very rare. 22,23However, the coexistence of all 3 disorders -an ARD, a thymoma, and PRCA -in the same patient is extremely rare.5][26][27] However, for only 2 of them, an ARD was diagnosed concurrently or prior to a thymoma and PRCA. 12,19Herein, we reported on a case (case 1) of a patient with the SLE-thymoma-PRCA triad.The patient developed PRCA and a thymoma 9 years after being diagnosed with SLE.All the patients in the 3 cases were females aged 48, 60, and 63 years, and they had SLE for 3, 9, and 9 years, respectively.Therefore, PRCA might be associated with an ARD and a thymoma, particularly in older patients who have an ARD disease course with a long duration.We speculate that PRCA may be associated with a thymoma, although there is no significant relationship between the occurrence of PRCA and the pathological type of thymoma.Searching for a thymoma is necessitated if a patient with ARD experiences PRCA.
The therapeutic strategy for ARDs combined with thymomas varies, with an uncertain outcome.Underlying conditions involving ARDs and thymomas should be treated.A thymectomy or gamma irradiation of the thymus gland may be performed for a thymoma.Neither chemotherapy nor irradiation is beneficial for the treatment of ARDs. 8,28The immunologic effects of a thymec-tomy for an ARD are also not clear.Several reports have documented the appearance, exacerbation, or remission of an ARD after a thymectomy. 15[13][14][15][16]18 In one of these cases, the patient with pSS was deemed to be in remission with surgery alone. 18However, for the patients who were diagnosed with an ARD before the thymoma, none achieved remission with surgery alone.Medicines such as corticosteroids, cyclophosphamide, or cyclosporine should also be used to treat ARDs.In spite of this, most patients experience an exacerbation, or their disease becomes refractory to treatment. 6,7,11,12As for our 1 st case, the patient did not undergo surgery, and her SLE and PRCA were deemed stable.As for our 2 nd case, the patient's condition worsened secondary to massive proteinuria and vein thrombosis several months after the thymectomy.It has also been reported that patients with SLE, a thymoma, and PRCA died of a pulmonary embolism after having a thymectomy. 27Therefore, a thymectomy or radiation would be effective for helping patients achieve remission with an ARD if the ARD were concurrently diagnosed with a thymoma; however, if the ARD were diagnosed prior to the thymoma, then in addition to treatment for the thymoma, a corticosteroid or immunological inhibitor should be used to help obtain remission for the ARD.Sometimes rituximab, donor lymphocyte infusion (DLI), or hematopoietic stem cell transplantation (HSCT) could also be used to treat the complication, PRCA. 19,29We surmise that if a thymoma and an ARD occur simultaneously, the thymoma might exert a role in the development of ARDs, as seen with MG.A thymectomy or radiation might be helpful for achieving remission with an ARD.If the thymoma were to occur several years after the ARD, it would not be clear if the thymoma was the primary abnormality or the immunologic abnormalities seen in patients with an ARD would lead to thymus disorders and tumor development.A thymectomy or radiation is not always associated with remission from an ARD and might sometimes cause an exacerbation.It is necessary to study additional cases to elucidate the effects of thymectomy in ARDs combined with thymomas and to help provide additional guidance for treatment.
In conclusion, we reported 2 cases and compiled a series of cases involving an ARD combined with a thymoma.The data indicated that ARDs can coexist with thymomas and that a thymoma should be included in the differential diagnosis if a patient with an ARD complains of PRCA.The result of a thymectomy for a patient with an ARD can be unpredictable.Indeed, ARDs involve a multisystem disease with heterogeneous and varied manifestations.Therefore, study of additional cases is necessitated for exploring issues related to ARDs and thymomas.

Fig. 1 .
Fig. 1.Computed tomography of the chest showing a mass in the anterior mediastinum (case 1)

Fig. 3 .
Fig. 3. Computed tomography of the chest showing a mass in the right anterior mediastinum (case 2)