Myelodysplastic syndrome presenting as a Behçet’s-like disease with aortitis

Abstract

A 46-year-old Hispanic man presented with fever, genital ulcers, left eye redness and chest pain. Physical examination was notable for a healed oral ulcer and scrotal ulcers, and bilateral superficial thrombophlebitis. He was found to have new-onset pancytopenia. CT of the chest showed pericardial and pleural effusions and rapidly progressing inflammation of the aortic arch and ascending vessels. Although the patient had Behcet’s disease (BD)-like symptoms, pancytopenia could not be explained by the diagnosis, prompting a bone marrow biopsy which showed myelodysplastic syndrome. This report highlights the importance of excluding alternate disorders before making a diagnosis of Behcet’s disease if atypical, BD-incompatible or incomplete constellations of symptoms and findings are present.

Background

Behçet’s disease (BD) is a clinical diagnosis. No definitive diagnostic tests are available. Given its multisystem character, many disorders can mimic BD even to the point of having patients formally fulfil International Study Group (ISG) Criteria—the currently most widely accepted diagnostic criteria for BD.¹ Therefore, making a diagnosis of BD requires thorough exclusion of such mimics, some of which can be life-threatening and may require treatment very different from that of BD. Our case of a patient with myelodysplastic syndrome (MDS) whose malignancy-associated autoimmune manifestations mimicked BD illustrates this problem.

Case presentation

A 46-year-old Hispanic man presented with fever, orogenital ulcers and chest pain. Two weeks prior to admission, the patient developed painful boils over his anus, scrotum and penis, subjective fever, chills and night sweats. He subsequently developed left eye pain and redness, was diagnosed with ‘uveitis’ and treated with prednisolone and cyclopentolate eye-drops. The patient then developed increasing fatigue, back pain and chest tightness. He described the chest pain as positional, worse in the supine position and improved with sitting up.

The patient also had a history of non-Hodgkin’s lymphoma (NHL) status post (s/p) chemotherapy and autologous bone marrow transplantation in 1990. At that time, he had developed a panniculitic rash that improved and ultimately disappeared with control of his NHL. At the time of presentation, the patient was not on any medications. He had no family history of autoimmune diseases. He was an active smoker. There was no history of significant alcohol or any drug use.

On examination, the patient was febrile to 39.5°C, tachycardic to 110 s, tachypneic with a respiratory rate of 40 beats/min, oxygen saturation 88% on room air and blood pressure 114/73 mm Hg. He had no lymph node enlargement or jugular venous distension. There was a healed ulcer at the palate (figure 1). His left eye was injected. Heart rhythm was regular; no murmurs were heard. There were decreased basilar lung sounds bilaterally. The abdomen was mildly distended, non-tender with hepatomegaly. He had two discrete areas of erythema with palpable cords on the extensor surface of the left arm. Two ulcers were noted on the scrotum (figure 2). His neurological and musculoskeletal examinations were normal. The patient was triaged to the intensive care unit given his respiratory distress and hypoxia.

Figure 1.

Clean-based oral ulcer located at the upper palate.

Figure 2.

Clean-based ulcer on the scrotum.

Investigations

The patient’s chest X-ray on admission was notable for a left lower lobe infiltrate. He was started on broad-spectrum antibiotics. Follow-up CT of the chest without contrast showed a moderate complex pericardial effusion, bilateral pleural effusions and a thick-walled descending aorta. MR angiography revealed thickening of the ascending aorta with concern for intramural haemorrhage with large vessel involvement. His initial laboratory workup was significant for new-onset pancytopenia with white cell count 3.9x10^9/L, haemoglobin 7.7 g/dL, Mean Corpuscular Volume (MCV) 96 FL, platelet count of 36x10⁹/L and a reticulocyte count of 0.8%. His direct antiglobulin test was positive. Albumin was low at 2.6 g/dL. He had a markedly elevated erythrocyte sedimentation rate of 100 mm/hour, C reactive protein >270 mg/L and a serum ferritin level of 1581 ng/mL. He was incidentally diagnosed with hepatitis C with a viral load >380 000 IU/mL.

Over the next 3 days, the patient continued to be febrile, and tachycardic with chest pain. He had a follow-up CT of the chest without contrast which showed an increase in stranding of the superior mediastinum, surrounding the arch and proximal arch vessels, increased thickening and stranding of the ascending thoracic aorta and aortic arch extending to the right innominate and right subclavian arteries, highly suggestive of rapidly progressing aortitis (figures 3 and 4). An upper extremities ultrasound revealed bilateral acute occlusive superficial thrombosis at the level of the basilic vein. Ophthalmology was consulted and a diagnosis of scleritis was made. There were multiple peripapillary cotton wool spots on retinal examination. There was no evidence of uveitis at this point.

Figure 3.

Thickening and stranding surrounding the wall of aortic arch seen on CT of chest without contrast. The arrows refer to thickening and stranding of the aortic wall.

Figure 4.

Thickening and stranding surrounding the wall of ascending thoracic aorta on CT of chest without contrast.

The patient underwent a comprehensive infectious and autoimmune workup for his large vessel vasculitis. Syphilis, HIV, CMV, Epstein-Barr virus (EBV), Varicella zoster virus (VZV), parvovirus, Histoplasma were ruled out through serological testing. ANA, antibodies to PR3 and MPO, and cryoglobulin were negative. ACE levels were within normal limits. The patient was HLA B27 and B51 negative. Given his unexplained pancytopenia, the patient underwent bone marrow biopsy which showed expansion of CD34 +myeloblasts (6.9%) accompanied by left-shifted maturation and hypogranulation among maturing myeloid elements, suggestive of myelodysplasia. Cytogenetic studies revealed 15 out of 23 cells with hypodiploidy with loss of chromosomes 3, 5, 9, 12 and 20 but no evidence of trisomy.

Differential diagnosis

Before the results of the bone marrow biopsy became known, the initial differential was broad and included infections (syphilis, CMV, EBV, fungal infections such as histoplasmosis, tuberculosis), malignancy (recurrent lymphoma, MDS) and autoimmune diseases (systemic vasculitis such as BD, aortitis due to spondyloarthropathy, other large-vessel vasculitis such as Takayasu’s, Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, systemic lupus erythematosus). Factors that steered away from accepting primary BD as the working diagnosis in this case at that point were the age at symptom onset, the pancytopenia and the presence of scleritis instead of uveitis on repeat eye examination.

Treatment

Given the rapid progression of his aortitis on admission, the patient was first treated with intravenous methylprednisolone 0.8 mg/kg while undergoing infectious disease and malignancy workup. His chest pain and eye symptoms improved with steroids. The patient was discharged with high-dose steroids (prednisone 80 mg orally daily) for rheumatology and haematology follow-up.

Outcome and follow-up

After 2 weeks, the patient was readmitted for steroid-induced hyperglycaemia. Given the risk of untreated aortitis, prednisone 80 mg orally daily was continued for 1 month while hyperglycaemia was managed with insulin. A repeat CT chest without contrast, after 1 month of treatment with prednisone 80 mg orally daily, showed resolved periaortic fat stranding and inflammation. Given the radiological improvement and absence of chest pain, shortness of breath or new ocular inflammation and genital lesions, prednisone was tapered by 10 mg every 5 days until 20 mg, and then decreased by 5 mg every 5 days afterwards. The patient did not develop any new symptoms of aortitis during or after the steroid taper. During this admission, he was also treated with two cycles of decitabine for MDS. He subsequently developed refractory anaemia and thrombocytopenia requiring frequent transfusions, as well as neutropenic fevers. Blood cultures grew Streptococcus mitis and a perianal abscess required drainage. The patient was treated with broad-spectrum antibiotics. His repeat bone marrow biopsy 3 months after the first biopsy revealed a hypercellular marrow, MDS with excess myeloblasts and deletion of EGR1 in 21% of cells. Cytogenetics showed 7 out of 25 hypotetraploid clonal cells with 5q deletion suggestive of poor prognosis.

After a prolonged hospital course of 3 months, the patient was followed by haematology as an outpatient with biweekly haemoglobin and platelet transfusions, as he was unable to generate adequate cell counts due to his hypercellular bone marrow. The patient was evaluated for haematopoietic stem cell transplantation (HSCT) but was determined not to be a candidate because of poor functional status and concern for inability to tolerate HSCT. In addition, the patient was not able to tolerate further chemotherapy due to transfusion requirements and was recommended palliative care. He passed away 6 months after the initial diagnosis of MDS from septic shock, renal and respiratory failure.

Discussion

MDS is a heterogeneous group of clonal haematopoietic stem cell disorders characterised by ineffective haematopoiesis and pancytopenia. MDS develops when a clonal mutation predominates in the bone marrow often causing it to be hypercellular. There is evidence that a dysregulated immune system may play a role in the cytopenia,^{2 3} supported by the fact that 10%–20% of patients with MDS have associated autoimmune phenomena.^{2 4 5}

MDS is frequently associated with a wide range of autoimmune diseases such as Sweet’s syndrome, relapsing polychondritis, polymyalgia rheumatica, Sjogren’s syndrome, systemic lupus erythematosus, seronegative arthritis and systemic vasculitis.^{6 7} Mekinian et al⁵ described the largest series to date of 123 patients with MDS-associated systemic inflammatory and autoimmune diseases (SIADs).⁵ They found the diagnoses of SIADs and MDS were concomitant in 38 (31%) patients. SIADs were classified as systemic vasculitis in 39 (32%) cases, connective tissue disease in 31 (25%) cases and inflammatory arthritis in 28 (23%) cases. Among the vasculitic diseases, polyarteritis nodosa and giant cell arteritis were most frequent. There were six cases of possible BD which were reported to have shown ‘incomplete’ criteria. No reference was made to the specific type of criteria applied.⁵

An association between BD and MDS has been proposed but is more likely to represent the association of BD-like autoimmune phenomena rather than a true link between the two disorders.

Steurer et al⁸ described two case reports of patients with MDS found to have aortitis.⁸ The first patient was a 67-year-old man who presented with malaise, fever, night sweats, arthritis and was found to have pancytopenia and massive thickening of the entire aorta, and a bone marrow biopsy consistent with refractory anaemia with excess blasts (RAEB). The second case was a 60-year-old man with RAEB type 1 who presented with malaise, fever and on CT showed vasculitic changes of the aortic arch and brachiocephalic trunk. Lopez et al described a 52-year-old woman who presented with chest pain and was found to have aortitis involving the aortic arch and descending thoracic aorta, as well as pancytopenia found to be caused by RAEB-t (Refractory anemia with excess of blasts in transformation).⁹

In addition to large vessel vasculitis described in the above cases, our patient also presented with other potentially Behcet’s-compatible symptoms such as oral and genital ulcers—although not recurrent— and bilateral superficial thrombophlebitis. There is a body of literature from Asia describing an association of MDS with trisomy 8 and a BD phenotype.^10–19 Most of the subjects described in these reports presented with intestinal ulcerations as the presenting manifestation of a BD phenotype associated with MDS.^10–19 In fact, patients with BD phenotype associated with MDS had a significantly higher prevalence of intestinal lesions as a symptom of Behcet’s compared with patients without MDS.¹⁴ In a review of 54 Japanese cases of MDS-associated ‘BD’, HLA B51 was reported to be positive in 36.7% of the cases, which is a lower frequency than in patients with BD from other endemic populations (eg, 54.9%–60% in Turkey). They also found a lower frequency of eye lesions (11.1% vs 69%) in MDS-associated BD phenotype compared with BD.⁴ These features may argue against a true association of the two disorders or represent referral bias at the centres involved. Of note, only two cases with an MDS-associated ‘Behcet’s’ phenotype presented with large vessel vasculitis.¹⁴

The constellation of genital ulcers, oral ulcers, inflammatory eye disease, superficial thrombophlebitis and aortitis in our case clearly had features of BD. However, several observations steered away early from accepting primary BD as a working diagnosis and led to the search for another underlying disorder: (1) The ocular phenotype of BD is uveitis which typically evolves into a bilateral panuveitis over time. Scleritis—although reported in some studies—is not a directly BD-compatible ocular phenotype, especially if not accompanied by coexisting intraocular inflammation (uveitis) causing a spillover phenomenon that gives rise to scleral inflammation. The presence of isolated scleritis should therefore skew considerations away from BD in most cases. (2) The age of onset of this patient’s autoimmune BD-like manifestations is atypical, as most patients with BD manifest in the second and third decades of life. The disease has an overall tendency to subside with increasing age. (3) Pancytopenia is not a feature of BD and—if present—should not be perceived as a BD-related ‘autoimmune’ manifestation. It requires an independent workup, often including a bone marrow biopsy.

Aortitis is a well-established feature of BD and one of its rare manifestations.²⁰ If present, involvement of the abdominal aorta is more frequent than that of the thoracic segment of the aorta. Additionally, pericardial and pleural effusion would need further explanation in this case, given their rarity in BD.

The case described here underpins the notion that BD is a clinical diagnosis and ISG criteria—or any other diagnostic criteria—need to be applied carefully and cautiously to limit the risk of misdiagnosing BD mimics as BD. This is of particular importance in most parts of the Western world, where even rare manifestations of some BD mimics may be far more prevalent than BD itself. A patient with Crohn’s disease, for example, may present with uveitis, recurrent oral ulcers and erythema nodosum, and thus formally fulfil ISG criteria, when these symptoms in fact represent extraintestinal manifestations of inflammatory bowel disease, rather than BD. Similar considerations are conceivable in MDS or other malignancy-related autoimmune phenomena, as well as in a wide range of other disorders. As stated by the ISG authors, ISG criteria should count for a diagnosis of BD only in the ‘absence of other clinical explanations’.¹ A judgement as to what is another appropriate clinical explanation will depend strongly on the clinician’s familiarity with both the target disease—BD—and its mimics in the the respective population. Therefore, problems with the application of the criteria often arise when providers are not well-acquainted with the phenotype and natural course of BD. This may lead to the erroneous interpretation of findings, which seem to be compatible with ISG criteria, when in fact they are not, or the application of ISG criteria when this is not warranted, that is, when more likely explanations for their occurrence in the specific clinical context exist. The latter is often the case when the findings represent rare manifestations of otherwise common diseases that are overlooked, not considered or not pursued aggressively enough. Some typical examples for the former are the mistaken inclusion of BD-atypical or incompatible ocular phenotypes instead of uveitis as a criterion, the inability to correctly interpret a pathergy test or to determine the significance of a skin rash to be counted towards a diagnosis of BD.

Our patient received glucocorticoids for treatment of his aortitis and responded quickly with resolution of periaortic fat stranding and inflammation as well as complete cessation of all clinically detectable extravascular autoimmune phenomena. First-line treatment for MDS-associated SIADs consisted of steroids, and response rates have been high (83%) as previously reported.⁵ Similar to previous reports, the treatment of SIADs had a limited effect on MDS cytopenias, and complications related to immunosuppression, in particular recurrent infections with sepsis, posed a problem in our case and in other reported patients. It is conceivable that successful treatment of MDS as the underlying disorder may confer a benefit with regard to the evolution, progression and outcome of SIADs. While MDS-targeted therapeutic options were limited in our case, promising data for a role of treating SIADs through MDS-targeted therapies exist. Especially noteworthy in this regard is the role of azacitidine (a DNA demethylating agent), which may be able to cause remission in SIADs. Response of SIADs to azacitidine was observed in 19 out of 22 (86%) patients with MDS in a retrospective study, leading to reduction of steroids in 63% in these patients.²¹ Both azacitidine’s reduction of the underlying immunogenic burden of MDS by apoptosis and its immunomodulatory effects may play a role in the observed remission of autoimmune diseases associated with MDS. Azacitidine can expand regulatory T cells, and decrease inflammatory cytokines such as interleukin-6.^{22 23} As such, azacitidine may be considered as a useful steroid-sparing treatment agent for patients to treat MDS with associated autoimmune diseases. Because our patient had a rapid response to steroids, it is difficult to dissect possible chemotherapy versus steroid-related therapeutic effects on his aortitis. Our patient also had MDS with poor prognostic features, and a short survival of 6 months limiting therapeutic options for his MDS. Interestingly, MDS associated with autoimmune diseases had been found to have worse baseline prognostic features, including higher bone marrow blast percentage and poorer karyotype, than MDS without SIADs as reported by Mekinian’s group. This experience would be in line with our patient described. However, overall survival in MDS patients with versus without SIADs was found to be similar in the study by Mekinian et al.⁵

In conclusion, immunogenic forms of malignancies such as MDS can mimic BD. Such autoimmune manifestations pose the risk to be diagnosed erroneously as stand-alone disease entities, masking the underlying malignant process. It is therefore of utmost importance to address unexplained, atypical or incomplete features in the presentation of such patients to reach a correct diagnosis of the causative disorder to which treatment should be targeted.

Learning points.

• Patients with myelodysplastic syndrome (MDS) can manifest with a wide variety of autoimmune disorders including systemic vasculitis. Patients may manifest with Behçet’s disease (BD)-like features mimicking BD.

• BD is a clinical diagnosis. A thorough workup is needed to rule out BD mimics when the presentation is atypical, incomplete or accompanied by findings not recognised to be part of the BD disease spectrum.

• Patients with BD mimics may fulfil diagnostic criteria for BD (International Study Group criteria). These criteria apply only if there is no alternative explanation for the patient’s presentation.

• Some BD mimics represent potentially life-threatening diseases, such as MDS.

• Treatment of MDS may have an effect on the resolution of associated autoimmune diseases. In addition, MDS with systemic inflammatory and autoimmune diseases (SIADs) have poorer prognostic features than those without SIADs.