A tale of Mabs and travel. Alex Tai Austin ID registrar

Transcription

1 A tale of Mabs and travel Alex Tai Austin ID registrar

2 HOPC 36 year old gentleman presents with a 1 month history of night sweats loss of weight (9kg) palpitations heat intolerance intermittent productive dry cough Recent 1 month overseas trip: Egypt > Dubai > Singapore

3 Past Med Hx Ankylosing Spondylitis Previous NSAIDs Infliximab for 10 years Now on Golimumab for 5/12 Med Hx Golimumab 50mg s/c every 1/12 NKDA

4 Social Hx Works in financial banking Has travelled extensively over the last 2 years for work Egypt; India; The gulf states No alcohol consumption or ilicit drug use Lives at home with wife and children Born in Australia Family of Egyptian background Frequent overseas trip to visit family in Egypt No exotic hobbies

5 On further Hx taking Had returned from overseas the week prior to presentation to the Austin Due to ongoing symptoms, was advised by sister who was a GP to present to hospital for a work up

6 O/E HR 84 RR 24 T 36.5 BP 127/80 Sats 99%RA Neck: Non tender thyroid> Small goitre Chest: Clear breath sounds on auscultation Heart: DHS. Nil added Abdomen: Soft, non tender. No organomegaly General: No stigmata of an autoimmune disease

7 Initial investigations Basic bloods FBE 150/6.4/312 U+Es NAD LFTs NAD CRP 35.7 ESR 30 Thyroid function tests TSH 0.01 T (12-22) T3 9.1 ( ) Thyroid antibodies normal

8 Chest imaging

9 Palpitations+ Drenching night sweats + Weight loss + Heat intolerance + Intermittent dry cough + Dypsnoea Chest imaging: mediastinal/hilar lymphadenopathy Recent overseas trip for 1 month Multiple overseas trip in his lifetime Differentials?? Hyperthyroidism 36 year old Australian born man On long term TNF-α-inhibitor therapy

10 Progress Admitted Respiratory isolation Review by endocrinology Propanolol Thyroid uptake scan requested CT chest to further define mediastinal lymphadenopathy

11 Thyroid uptake scan Overall reduced uptake in thyroid gland. Findings would be consistent with thyroiditis

12 CT chest Mediastinal and hilar lymphadenopathy

13 CT chest Mediastinal and hilar lymphadenopathy Mediastinal and hilar lymphadenopathy

14 CT chest Focal pulmonary ground-glass and tree-in-bud opacity in the right upper and middle lobes

15 CT chest Focal pulmonary ground-glass and tree-in-bud opacity in the right upper and middle lobes

16 Further Investigations Serology Hepatitis A IgM -ve Hepatitis B sab ve sag -ve Hepatitis C Ab ve HIV ve Histoplasmosis -ve QFG ve ACE level normal

17 Progress Increasing suspicion for pulmonary TB + LN TB Respiratory review: For inpatient diagnostic bronchoscopy

18 Bronchoscopy results Bronchial washings (RUL) <1ml moderately blood stained fluid (RUL) 20mls mucoid fluid Micro Gram: + polys ++NURTF Fungal wet prep: No fungal elements AFB smear negative > GeneXpert negative Culture: NURTF Cytology No malignant cells identified

19 Progress Ongoing night sweats, dypsnoea and lethargy on the ward post bronchoscopy Respiratory and ID discussion: Repeat bronchoscopy + Endobronchial Ultrasound (EBUS) + Fine Needle Aspirate (FNA) of mediastinal lymph node

20 Bronchoscopy + EBUS + FNA LN bx FNA of mediastinal lymph node Gram: Bacteria not seen Culture: Scanty skin flora AFB smear negative> Gene Xpert negative Flow: There was no evidence of clonal B-cell or abnormal T-lymphoid population But on further review of the cytology slide.

21 15C509 EBUS FNA cytology background lymphocytes Possible granuloma

22 Multinucleated giant cells Possible granuloma comprising epithelioid histiocytes

23 The classic ID referral questions We can see granulomas on histopathology of x specimen.. Is this TB? We want to rule out infection before giving steroids What further tests do we need to do? This is not our problem anymore, please take over care of the patient

24 Palpitations+ Drenching night sweats + Weight loss + Heat intolerance + Intermittent dry cough + Dypsnoea Chest imaging: parenchymal changes in the RML/RUL and mediastinal/hilar lymphadenopathy Thyroiditis Recent overseas trip for 1 month Multiple overseas trip in his lifetime What would you do next? X2 bronch washings + EBUS FNA mycobacteria culture smear negative genexpert negative 36 year old Australian born man On long term TNF-α-inhibitor therapy

25 Progress We elected to watch and wait Last dose of Golimumab just before admission- Withheld at least until follow up cultures of bronchoscopy specimens Discharged home post bronchoscopy + EBUS with outpatient follow up x2 BAL fluid AFB smear ve

26 Review 1 week post discharge Ongoing constitutional symptoms: night sweats/lethargy ongoing dyspnoea and intermittent dry cough Bronchial washings x2 + EBUS FNA Mycobacteria culture negative at 1 week Ongoing discussion with patient regarding empirical TB treatment Golimumab ceased by concerned rheumatologist

27 Persisting hilar lymphadenopathy Repeat Chest imaging

28 Review 6 weeks post discharge Improved constitutional symptoms Chest still slightly tight Improved TFTs and inflammatory markers But.severe symptoms related to AS Back pain Unable to mobilize effectively Unable to work Bronchial washings x2 + EBUS FNA Mycobacteria culture negative at 6 weeks

29 CRP

30 Repeat imaging 6 weeks later

31 Improved mediastinal lymphadenopathy Improving constitutional symptoms Worsening symptoms related to AS Slowly improving TFTs What would you do next? X2 bronch washings + EBUS FNA mycobacteria culture negative at 5 weeks 36 year old Australian born man On long term TNF-α-inhibitor therapy

32 Progress NSAIDs eventually failing to aid symptoms Crippled by AS symptoms TB cultures remain negative at 7 week mark Trial of oral prednisolone Symptoms of AS improve TB cultures remain negative at 8 week mark Infliximab eventually recommenced Symptoms have AS practically melted away Only remaining symptom is minor lethargy

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35 Conclusion Sarcoidal drug reaction secondary to Golimumab Weight loss Mediastinal lymphadenopathy Parenchymal lung changes Thyroiditis Night sweats Lethargy Intermittent dry cough Histopath showing granulomas Dyspnoea

36 Reversible when drug withdrawn Rule out infections ie TB Steroid responsive Sarcoidal drug reaction secondary to Golimumab

37 TNF-α-inhibitors Etanercept Infliximab Adalimumab Certolizumab Golimumab

38 Sarcoidosis Granulomatous disorder of unknown etiology Affects multiple organs, namely lungs Histological feature is non caseating or epitheliod granuloma Diagnosis made after other causes of granulomatoses are excluded

39 Granuloma formation in sarcoidosis Broos, C. E., van Nimwegen, M., Hoogsteden, H. C., Hendriks, R. W., Kool, M., & van den Blink, B. (2013). Granuloma Formation in Pulmonary Sarcoidosis. Frontiers in Immunology, 4, 437. doi: /fimmu

40 TNF-α and treatment of sarcoidosis TNF-α is a cytokine produced by Th1 cells, antigen presenting cells and keratinocytes Exists in both membrane bound and more potent soluble forms 2 receptors: p55 and p75 which bind to TNF-α TNF-α is thought to play a central role in the pathogenesis of sarcoidosis Because of that, the TNF-α monoclonal abs have been used for treatment

41 Sarcoid like granulomatous reactions following TNF-α-inhibitors Paradoxical effect where TNF-α inhibitor therapy has resulted in onset of sarcoidal reaction The first case described in Review of the literature suggest at least 65 cases, all case reports and case series Estimated prevalence 0.04% 2 1 PENO-GREEN, L., LLUBERAS, G., KINGSLEY, T. & BRANTLEY, S Lung injury linked to etanercept therapy. Chest, 122, DAIEN, C. I., MONNIER, A., CLAUDEPIERRE, P., CONSTANTIN, A., ESCHARD, J. P., HOUVENAGEL, E., SAMIMI, M., PAVY, S., PERTUISET, E., TOUSSIROT, E., COMBE, B. & MOREL, J Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases. Rheumatology (Oxford), 48,

42 MIYAGI, R., IDEGUCHI, H., SOGA, T., YAMAKAWA, Y., OTSUKI, H., NIINO, H., SHIINA, T., UEDA, A. & ISHIGATSUBO, Y Development of pulmonary and cardiac sarcoidosis during etanercept therapy. Int J Rheum Dis, 17,

43 First case of sarcoidal drug reaction secondary to a Etanercept

44 First fatal case of suspected sarcoidal reaction to etanercept

45 Disease reoccurrence with rechallenge

46 Theories of pathogenesis Hypothesized to be caused by disruption of the fine balance of the main cytokines involved in granuloma formation Suppression of TNF-α leads to increase in IFNα 1 Modulate a CD4+Th1 cytokine response 2 The Psoriasis and rheumatoid arthritis examples 2 1 PALUCKA, A. K., BLANCK, J. P., BENNETT, L., PASCUAL, V. & BANCHEREAU, J Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci U S A, 102, MASSARA, A., CAVAZZINI, L., LA CORTE, R. & TROTTA, F Sarcoidosis appearing during anti-tumor necrosis factor alpha therapy: a new "class effect" paradoxical phenomenon. Two case reports and literature review. Semin Arthritis Rheum, 39,

47 Infliximab Etanercept Completely inhibits both p55 and p75 mediated TNF-α receptors Preserves the function of the p75 mediated TNF-α receptor More complete TNF neutralization Partial TNF-α neutralization Increases lysis of CD4 & CD8 Reduces IFN-γ Increases production of IFN-γ

48 Diagnosis 1. Chronology between TNF-α-inhibitor and disease is always compatible 2. Discontinuation of the TNF-α-inhibitor reverses/halts disease progression 3. Recurrence of symptoms and pathology could be observed when a TNF-α-inhibitor (the same or different one) was restarted AU, S., MIRSAEIDI, M., ARONSON, I. K. & SWEISS, N. J Adalimumab Induced Subcutaneous Nodular Sarcoidosis; A Rare Side Effect of Tumor Necrosis Factor-alpha Inhibitor. Sarcoidosis Vasc Diffuse Lung Dis, 31,

49 Treatment When a TNF-α-inhibitor in required to control underlying disease, a switch from a soluble receptor format to monoclonal antibodies and the converse can be attempted based on the available literature 1 Relapse can still occur even after a switch 1 Steroid therapy 1 MIYAGI, R., IDEGUCHI, H., SOGA, T., YAMAKAWA, Y., OTSUKI, H., NIINO, H., SHIINA, T., UEDA, A. & ISHIGATSUBO, Y Development of pulmonary and cardiac sarcoidosis during etanercept therapy. Int J Rheum Dis, 17,

50 Golimumab (MIMS)

51 Golimumab (Simponi Drug Information) sarcoidosis

52 Golimumab and sarcoidal drug reactions Our case is the first known case in the literature to have a sarcoidal reaction (hilar lymphadenopathy, night sweats, weight loss) secondary to Golimumab Along with the current literature describing sarcoidal reactions with Etanercept, Adalimumab and Infliximab, this is suggestive of a class effect

53 Lessons When suspecting TB/infection in patients with a sarcoid-like illness on TNF-α-inhibitors, have a high index of suspicion for a drug reaction Diagnosis of exclusion Rule out treatable and serious conditions such as TB or histoplasmosis A drug reaction is proven by removing the offending drug and observing Consideration of steroids or switching to a different TNF-α-inhibitors

54 Granulomatous disease following TNF-α inhibitors

55 Acknowledgements Professor Paul Johnson Dr Sarah Garner Dr Alison Skene The patient The Austin ID team