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Abstract
Behçet disease is a relapsing multiorgan inflammatory disorder characterised by mucocutaneous, opthalmic, neurological, vascular and gastrointestinal involvement. We report an intriging case with rare manifestations of myositis and myocarditis, and the first reported occurrence of an immunocompromised-associated infection (polymicrobial necrotising fasciitis) without immunosuppresive therapy use in this presumably hyperimmune disorder.
Lessons from practice:
1. Behçet Disease is a rare autoimmune condition with significant geographical variation in its distribution and is most prevalent in people of Turkish background.
2. Behçet disease is a systemic disease with predominant symptoms of oral ulcerations, genital ulcerations and uveitis. Other systemic involvement include neurological, gastrointestination, rheumatic, dermatological manifestation. Less common but well described manifestation include muscle and cardiac involvement.
3. The unexplained manifestation of Type 1 necrotising fascitis in this patient suggests that immune dysregulation in Behçet disease could contribute to primary immunosuppression. It is important to maintain high viligance for risk of infection in Behçet disease.
Clinical Record
A 40-year-old woman presented to hospital for investigation of progressive malaise, anorexia and generalised proximal myalgia over 6 days with an elevated serum creatine kinase [CK] of 3550 U/L (reference range [RR] < 145). She is of Spanish and Turkish ethnic background. Her medical history included transfusion-related Hepatitis C Virus (HCV) infection, lower limb deep vein thrombosis with Factor V Leiden mutation and depression. She denied any infective symptoms, recent trauma or stenuous exercise, rash or athralgias. Physical examation was unremarkable except for proximal generalised myalgia without weakness. Laboratory investigations initially revealed a normal erythrocyte sedimentation rate and C-reactive protein (CRP).
Over the next 72 hours, she developed an acute bilateral polyathropathy of the wrist and metacarpalphalangeal joints. Multiple cutaneous manifestations were observed including (1) a rapidly evolving erythema nodosum-like rash over the legs which later progressed into a purpuric non-blanching rash with fluctuant subcutaneous oedema, (2) multiple oral aptheous ulcers and (3) perioral acneiform papular nodules.
Further laboratory studies showed mildy raised inflammatory markers and a normalising CK of 428 U/L. The results of investigations for differential diagnoses were unremarkable. (Table 1) Multiple skin biopsies showed a neutrophilic-dermatosis like reaction.
On day 6, she developed a mildly tender natal cleft excoriation which progressively became pustular over 2 days with a dramatic increase in CRP >380mg/L and worsening renal function. She remained systemically well. A wound swab grew methicillin-sensitive staphylococcus aureus. Oral flucloxacillin and metronidazole were commenced. MRI showed enhanced T2 signals in the presacral fascia correlating to the sacral wound. A biopsy of the natal cleft wound showed similar findings to previous skin biopsies.
Simultaneously, a pathergy-like reaction was noted with previous intravenous-cannula and biopsy sites becoming pustular. At this point, further clinical history revealed a 5 year history of recurrent oral and gential ulcerations up to 4 episodes a year. A clinical diagnosis of Behçet disease was made. Subsequent HLA-B51 testing and ophthalmological examination were unremarkable.
On day 10, she deteriorated acutely becoming hypotensive and hypoxic. Computer tomography (CT) pulmonary angiography revealed bilateral pneumonia. Serum white cell count and CK increased substantially from 11.0 x109/L to 37.2 x109/L (RR 4.0 – 11.0) and 233 U/L to 3715 U/L respectively in 4 days. She was intubated, commenced on broad-spectrum antibiotics with systemic glucocoticoid and inotropic support. A further CT of the pelvis revealed numerous sacral subcutaneous gas locules and fluid. Multiple debridement procedures achieved drainage of large amount of pus and excision of the necrotic tissue. Sacral necrotising myofasciits was confirmed on a frozen section specimen showing extensive necrosis within subcutis, fascia and skeletal muscle with numerous mixed bacteria.
Post-operatively, a substantially elevated cardiac Troponin-I level of 51.33 ug/L (RR <0.04) with correlating precordial ST segment depression and biphasic T waves electrocardiogram (ECG) changes were noted. A trans-thoracic echocardiogram (TTE) showed dyskinetic septum, inferior and anterior wall with a reduced left ventricular ejection fraction of 25% on a background of previously normal cardiac function. A subsequent angiogram revealed normal coronary anatomy without flow limiting lesions. Apical ballooning was not seen on LV ventriculogram. She made a slow but steady recovery after a prolonged Intensive Care Unit (ICU) admission despite further suffering from an unheralded ventricular fibrillation cardiac arrest three weeks later.
The remainder of her acute admission was uneventful. Her oral ulcers, myalgia and cutaneous rashes progressively resolved with systemic glucocorticoids and azathioprine. An Automatic Implantable Cardioverter-Defibrillator was inserted after a follow-up TTE demonstrated persistent moderately-severe segmental systolic and diastolic dysfunction with features of dilated cardiomyopathy (DCM). Her cardiac dysfunction remained stable with a left-ventricular ejection fracture of 24% on TTE at 4 years follow-up.
Discussion
Behçet disease (BD) is a rare multiorgan chronic inflammatory disorder of unknown etiology with a strong geographical variation. The highest prevalence is noted in countries along the ancient silk road extending from Japan to the Middle East. Turkey is known to have the highest prevalence with 421 per 105 population. Australia has a reported prevalence of only <1 per 105 population1. The lack of a universally recognised pathognomonic test and an increasing insight into the clinical variation of BD has resulted in the development of a number of diagnostic critieria to define BD. Well-known critieria include the International Study Group (ISG) criteria developed in 1990 which requires the presence of oral ulcers and 2 minor features from gential ulcers, characteristic skin lesion (eg. Erythema nodosum, acneiform papulopustular lesions), characteristic ocular lesions (uveitis, retinal vasculitis) and positive pathergy test. In recent years, the International Criteria for Behçet Disease (ICBD) was proposed to replace the ISG critieria and further incorporates the increasingly recognised neurological, vascular and gastrointestinal manifestations2. To date, BD remains a challenging clinical diagnosis to make. In our patient, in addition to reaching a clinical diagnosis with both set of criteria, the rare but well recognised manifestations of myositis and myocarditis were also seen.
Myositis is an uncommon non-orbital association of BD with only 14 cases previously reported in the English literature3-5. The majority of cases are localised myositis predominantly presenting as recurrent focal tenderness in the lower limbs interestingly without an associated creatine kinase (CK) rise. Comparatively, generalised myositis in BD presents as a progressive myalgia with weakness accompanied by an elevated CK. The generalised myositis in our patient correlates well with the features described in the literature. Diagnoses of myositis in the literature were made via either muscle biopsy or MRI. Histological studies have suggested an initial netrophil-mediated vasculitis and a subsequent lympho-monocytic infiltration to be the main pathology in BD myositis5. Treatment is immunosuppression-based and involves corticosteroids, with or without colchicine and cyclosporin, often with dramatic resolution of symptoms.
Cardiac involvement in BD is another uncommon but well recognised manifestation. Abnormalities can include pericarditis, valvular insufficiency, intracardiac thrombosis, endomyocardial fibrosis, coronary arteritis with myocardial infarction, coronary aneurysm, myocarditis and cardiomyopathy. A recently published large series of 807 BD patients showed cardiac involvment was present in up to 6% of BD flares, with the most frequent being pericarditis6. The prognosis is worse in the prescence of cardiac involvment with mortality up to 15.4% over 3 years compared to 5.4% otherwise. Among the cardiac manifestations, myocarditis and DCM are rare with only 5 cases of DCM in BD reported worldwide7. In our patient, a clinical diagnosis of probable myocarditis was made given the contemporaneous biochemical, ECG and ultrasonographic evidence of acute myocardial dysfunction without coronary abrnomalities during the BD flare. Takotsubo cardiomyopathy is a possible alternative diagnosis. However the absence of characteristic apical ballooning on angiogram and persistent combined LV systolic and diastolic dysfunction at 4 year follow-up suggest takotsubo cardiomyopathy is less likely. The final and most notable feature in this case is the spontaneous occurrence of Type 1 polymicrobial necrotising fasciitis (NF). Unlike Type 2 (monomicrobial) necrotising fasciitis, Type 1 NF mostly albeit not exclusively occurs in immunocompromised individuals8. Current theories of BD aetiology suggest a proinflammatory, Th1/Th17 based hyperactivation with complex genetic and environmental interplay as the principal pathogenic mechanism9. Examples of implicated genetic factors include HLA-B51 and the more recently described MHC class I amino acid residue, GIMAP (GT-Pases of immunity associated protein), complement copy variation and microRNA polymoprhism. Proposed environmental factors include exposure of bacteria (most extensively studied in Streptococcus sanguinis) and viral molecules such as Heat Shock Protein9.
Anti-inflammatory, immunosuppressive agents and biologic agents such as TNF-a anatognist are the standard therapeutic management of BD. Overall, rate of immunosuppressive use rate is reported to be as high as 59% among BD patients10.
While serious and opportunistic infections have been reported in BD patients with immunosuppressive therapy, a primary immunocompromised state has not been previously described as a possible primary feature of BD. In a study of 130 BD patients, the overall frequency of serious infections in BD patients receiving biologic theapries was similar to the reported rate in other diseases10. The development of Type 1 NF in our patient is admittedly multifactorial with potential contribution from the autoinflammatory dermatological involvement of BD compromising skin integrity. However the development of a severe immunocompromised-associated infection in a BD patient without immunosuppressive therapy nonetheless raises the question whether the underlying immune dysregulation may also predipose to immunnosuppression. Regardless whether this is a rare coincidence or the first described case of primary immunosuppression in BD, this case highlights the need for physicians to be highly viligant of serious infections in BD given immunosuppresive therapy is the accepted standard of care which itself poses a significant iatrogenic risk of infection.
This case illustrates many atypical features of Behçet disease and the challenges of diagnosing Behçet disease. Close attention should be given to the risk of infection in the treatment and presentation of Behçet disease.
