Roman Czubatyj M.D

Diego Vasquez M.D

Rheumatology Fellows 2

WSU/DMC/HFH

PULMONARY HEMORRHAGE COMPLICATING PULMONARY ARTERIAL ANEURYSMS IN A

YOUNG FEMALE WITH BEHCET’S DISEASE

YOUR PATIENT• 28 year old female, originally from Yemen, presents to the Emergency Room with

worsening shortness of breath and hemoptysis that started earlier that day.

• Patient has a 6 year history of Behcet’s disease that was diagnosed by recurrent oral ulcers, recurrent genital ulcers, arthritis, and recurrent panuveitis.

• This is her third admission within 6 months with hemoptysis. She was intubated on her second admission, only 2 weeks ago. She was treated with 1gm/day IV methylprednisolone for 3 days, and improved. Discharged on 2mg/kg daily of prednisone and 100mg daily of azathioprine.

• She has been on prednisone and azathioprine off and on since 2006, but recently was restarted after her first admission with hemoptysis

• Patient denies any other symptoms except for shortness of breath and hemoptysis. She states she has coughed up about ½ cup of blood.

• Past Medical History:

• Behcet’s Disease (diagnosed 2006)

• Recurrent oral and genital ulcers, recurrent uveitis, arthritis

• Complicated with Pulmonary arterial aneurysms

• Past surgical History

• None

• Allergies:

• No Known Drug Allergies

• Family History

• No rheumatologic disorders

• Social History

• No tobacco use

• No alcohol use

• No illicit drug use

• Sexually active with her husband

• One healthy child

• Home Medications

• Prednisone 2mg/kg/day

• Azathioprine 100mg Daily

HISTORIES

PHYSICAL EXAM

• Vital Signs: Blood Pressure: 111/70 mmHg, Pulse: 92 bmp, Respirations 20 per minute

• Temperature: 37.1 C, Pulse Oximetry: 100% on 2 Liters by Nasal Cannula

• General Appearance: No Acute Distress, Patient sitting up in bed, Responds appropriately to questions. Alert and Oriented to person, place and time

• HEENT: Pupils equally round and reactive, extra ocular muscle intact, external auditory canal within normal limits, oropharynx demonstrates no lesions, no erythema, neck is supple with no lymphadenopathy

• Respiratory: Inspection shows equal chest expansion, good respiratory effort, slight crackles at her lung bases bilaterally

• Cardiovascular: No visible heaves on inspection, Regular rate and rhythm, no murmurs, no rubs, no gallops. Peripheral pulses equal in upper and lower extremities

PHYSICAL EXAM

• Gastrointestinal: inspection reveals no scar, not distended, bowel sounds present in all four quadrants, no tenderness, no rebound, no guarding

• Genitourinary: No lesions present, normal female

• Musculoskeletal: no deformities present, all joints have good range of motion, no tenderness, synovitis, erythema. Good muscle tone throughout, 5/5 strength in upper and lower extremities

• Integumentary: No rashes present, no lesions

• Neurological: Cranial Nerves II-XII intact, no gross deficits

• Psychiatric: Cooperative

LABORATORY VALUES

• Sodium 137 mmol/L

• Potassium: 3.9 mmol/L

• Chloride: 102 mmol/L

• Carbon Dioxide: 31 mmol/L

• BUN: 15 mg/dL

• Creatinine: 0.46 mg/dL

• Glucose: 95 mg/dL

• Calcium: 8.7 mg/dL

• Magnesium: 1.8 mg/dL

• Prothrombin time: 13.7 sec

• INR: 1.04

• Partial thromboplastin time: 24 sec

• White Blood Cells: 6.8 K/ul

• 65% Neutrophils

• 24% Lymphocytes

• 10% Monocytes

• Hemoglobin: 11.1 g/dL

• Baseline: 12.8 g/dL

• Hematocrit: 33.4%

• MCV: 89.6 fl

• MCH 29.9 pg

• MCHC 33.4 g/dL

• RDW 18.5%

• Platelets: 333 K/uL

• Sed Rate, Westergren: 11 mm/Hr

• C-Reactive Protein: <0.3 mg/dL

IMAGING

Multifocal airspace disease which appears to be more confluent within the left mid-lung. Given the clinical history, underlying alveolar hemorrhage is again favored.

CT IMPRESSIONS• 1. Diffuse patchy lung opacities particularly in the left lower lobe consistent with

hemorrhage in the setting of hemoptysis. Although overall pattern of lung opacification has improved from previous CT, the pattern of resolution and recurrence by interval chest x-rays suggests that this hemorrhage is new.

• 2. Approximately 1 cm pulmonary arterial aneurysm versus pseudoaneurysm adjacent to the left hilum is decreased in size from prior examination. Separate aneurysms described on prior CTA examination have significantly decreased or resolved.

PREVIOUS CT SCAN

CLICK HERE TO SKIP

6 months ago

CT IMPRESSION

• 1. Numerous bilateral pulmonary artery aneurysm is as detailed above, the largest in the left upper lobe, compatible with history of Behcet's disease.

• 2. Thrombus is noted within most of the aneurysms with occlusion of several right lower lobe segmental arteries.

• 3. Peripheral, nodular opacities in the right lower lobe may represent small areas of infarct.

• 4. Ground glass opacity in the left upper lobe and bilateral lower lobes could represent atelectatic change, however, given history of hemoptysis, these also could represent areas of hemorrhage.

MANAGEMENT

• Patient was admitted and Rheumatology was consulted

• Rheumatology recommended starting methylprednisolone IV 1gm daily for 3 days

• Discussions with the patient regarding treatment options occurred at her last admission

• She is a young female who desires to have more children

• Safety and information about treatment options were shared with the patient

• She agreed that trying an anti-TNF would be best for her

• TB test negative

• After her 3 days of IV pulse steroids patient had resolution of her initial symptoms

• She was started on Infliximab 5mg/kg.

• She received her loading dose of infliximab at 0, 2, and 6 weeks

• Started on regular treatments at 8 week intervals

UPDATE (1 YEAR)• Patient continues to receive IV infusions of infliximab at 5mg/kg every 8 weeks

• Also taking azathioprine 100mg daily

• She has been symptom-free since her last admission (16 months ago)

• She has reported no side effects from the medication.

DISCUSSION

• Pulmonary arterial aneurysms, as part of vascular complications in BD are not as uncommon as previously thought. The reported prevalence is up to 30%, and these represent the most frequently fatal complication in BD occurring almost exclusively in young males4.

• Even though the etiology of BD is currently unknown, tumor necrosis factor-alpha (TNFα) has been involved in the pathogenesis of this disease5, being found locally and systemically elevated in BD6. Although the use of Infliximab to treat pulmonary aneurysms is increasing, there are no randomized controlled trials to confirm the reported findings.

• Infliximab is a chimeric monoclonal antibody specific for human TNFα, and administered by intravenous infusion. Infliximab is dosed by weight and is started at 3 to 5 mg/Kg, and titrated up to 8 mg/Kg. It is infused every 8 weeks after the initial induction is completed (0, 2 and 6 weeks).

• The response to Infliximab in severe vascular BD is impressive. There are multiple case reports7,8,9 that describe its use and quick resolution of the aneurysms as well as improvement in inflammatory markers and other disease manifestations.

• This is another case of refractory ocular and mucocutaneous BD complicated with pulmonary arterial aneurysms, that although responded initially to azathioprine and prednisone (decrease in aneurysm size) had recurrence of hemoptysis, skin and mucosal disease, which lead to initiation of Infliximab.

• Currently, she is in remission for over a year with regularly scheduled (every 8 weeks) infusions of infliximab at a dose of 5mg/kg, and also azathioprine 100mg daily.

• The peculiarity of our case is the gender of the patient. Being a young female that desires further pregnancies therapeutic options were limited, as cyclosporine and other immunosuppresants were eliminated as options.

• Furthermore, we believe that as the ethnicity and prevalence is changing with time, the disease characteristics by gender may also be changing.

CONCLUSION

• Behcet’s Disease (BD) is a rare, chronic disorder that is being recognized in more ethnicities than before.

• Treatment of the manifestation of this disease can be difficult and should be tailored directly to the patient. Prednisone, colchicine and azathioprine have shown benefit in treating this disorder.

• Recently TNF inhibitors, Etanercept and Infliximab, have been used. Etanercept has some clinical data for the use in mucocutaneous disease, but currently there are no randomized controlled trials for Infliximab.

• Currently, there are very few studies done with TNF inhibitors and BD. Other case reports have been published, but more research is needed.

REFERENCES• Hamzaoui K, Berraies A, Kaabachi W, Ammar J, Hamzaoui A. Pulmonary manifestations in Behcet Disease: impaired

natural killer cells activity. Multidiscip Respir Med. 2013 Apr 4;8(1):29..

• Seyahi E, Melikoglu M, Akman C, Hamuryudan V, Ozer H, Hatemi G, Yurdakul S, Tuzun H, Oz B, Yazici H. Pulmonary artery involvement and associated lung disease in Behçet disease: a series of 47 patients. Medicine (Baltimore). 2012 Jan;91(1):35-48.

• Bilgin G, Sungur G, Kucukterzi V. Systemic and pulmonary screening of patients with Behçet's disease during periodic follow-up. Respir Med. 2013 Mar;107(3):466-71. doi: 10.1016/j.rmed.2012.04.005. Epub 2012 Dec 21.

• Yazici H, Esen F. Mortality in Behçet's syndrome. Clin Exp Rheumatol 2008;26(5 Suppl 51):S138-40

• Alpsoy E, Akman A. Behçet's disease: an algorithmic approach to its treatment. Arch Dermatol Res 2009;301(10):693-702

• Turan B, Pfister K, Diener PA, Hell M, Möller B, Boyvat A, Ergin S, Villiger PM. Soluble tumour necrosis factor receptors sTNFR1 and sTNFR2 are produced at sites of inflammation and are markers of arthritis activity in Behçet's disease. Scand J Rheumatol 2008;37:135-41

• Schreiber BE, Noor N, Juli CF, Haskard DO. Resolution of Behçet's syndrome associated pulmonary arterial aneurysms with infliximab. Semin Arthritis Rheum. 2011 Dec;41(3):482-7.

• Adler S, Baumgartner I, Villiger PM. Behçet's disease: successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis. Arthritis Care Res (Hoboken). 2012 Apr;64(4):607-11.

• Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behçet's disease: analysis of published data on 369 patients. Semin Arthritis Rheum. 2011 Aug;41(1):61-70.