אחר התחלואה מעקב JIAבחולה הריאתית

ר מיכל גור"ד

ר יוסף ריבלין"ד

חיפה, מרכז רפואי כרמל

2014פ פברואר "חיפ

Case presentation

• S.R., 7 yrs old

• Twin pregnancy, born 37th wk, 2.335 kg

• Prenatal US – horseshoe kidney; severe

hydronephrosis (lt.) at birth → nephrostome 3wks

• Pulmonary: age 1m – hospitalization – RUL

pneumonia

• Age 2m – PICU – acute bronchiolitis RSV neg.;

severe, prolonged course; 27d in hospital; susp.

reflux & aspiration – treated with zantac

Case presentation – cont.

• Age 8m – Carmel Medical Center

• Severe, persistent respiratory symptoms – cough, dyspnea, wheezing; recurrent pneumonia

• No improvement with bronchodilators & steroids

• PE – dyspnea, tachypnea, audible wheezing; sat 98%; lungs - ↓ air entry, prolonged exp. with bilateral wheeze

• WBC 19500, 37.7% Neut.

• Inh ventolin, aerovent, budicort → some improvement

Case presentation – cont.

• Investigations:

UGI – normal, no reflux seen

Sweat test – normal

Ig’s – normal

CT – consistent with BO

• UTI (PsA & Klebsiella) – ciprofloxacin

• On discharge – mild exp. wheeze; Ventolin +

budicort

• Impression of chronic lung disease –

bronchiolitis obliterans due to early viral insult

Case presentation – cont.

• 5.12.07 – age 10m – nephrectomy of non-

functioning lt. kidney

• Uncomplicated course, discharged after 5d

• BUT – continuous respiratory symptoms; no

improvement with bronchodilators

• 3 wks later – severe exacerbation due to RSV;

ventolin + budicort, steroids (IV, oral), azenil

FUO• 7.08 – age 1.4 yrs – prolonged fever 38.5-40; no

other symptoms

• PE – swelling rt. wrist

• Inflammatory markers ↑↑ - WBC 20000, CRP 104

• FUO workup: CXR

Cardiac echography

Bone scan

Serology – EBV, CMV, resp. viruses, brucella, rickettsia, parvovirus, varicella zoster – all neg.

Bone marrow aspiration – marked lt. shift in myeloid lineage; culture neg.

Eye examination

FUO – cont.

• Abdominal US – chain of cysts in

retroperitoneum, 5-6cm; clear fluid

• Treated with zinacef → ertapenem; fever ↑

• Abdominal CT – elongated retroperitoneal cyst,

10x4x5.5 cm; watery content with fine septations

Cyst aspirated in Urology Schneider, but fever

persists…

Diagnosis

• Continued fever

• Inflammatory markers ↑↑↑ - WBC 57000-61000;

CRP 293

• Arthritis- wrists

• Rash – salmon-like

JIA – Juvenile Idiopathic Arthritis

JIA

• Pulse steroids, started Mtx

• Initial improvement, short term

• After 3m – increasing dyspnea; arthritis wrists

• Mtx stopped due to respiratory deterioration

JIA – cont.

• 24.11.08 – age 1.75 yrs:

• Pulse steroids

• Mtx stopped; started Enbrel (anti TNF) x1/wk

• Resp. deterioration – wheezing ↑, crepitations,

sat. 88%; ventolin + steroids – no improvement;

RSV pos. → adrenaline + fusid

• Fever ↑, pul. Infiltrates; Rocephin → i.v. resprim

→ preventive p.o. resprim

• Initial improvement…

JIA – cont.

• 3.09 – age 2 yrs – further deterioration

– Respiratory – dyspnea, unable to taper steroids

– Joints – cystic masses in ant. aspect of forearms

JIA – cont.

• Schneider – for investigation

• Lung scan – perfusion defects – apical & sup.

segment RLL; ventilation scan – normal

• Bronchoscopy – anomaly & narrowing of

medium + small airways → compatible with BO

• Shoulder US – irregular processes arising from

joints → synovial cysts; widened joint capsule

• CXR – hyperinflation; peripheral alveolar

infiltrates, mild pleural thickening

JIA – cont.

• UGI – reflux up to middle 1/3 of esophagus

• Cardiac echo – no pul. HT

• Sputum culture neg.

• Chest CT -

CT

Irregular ant border of ribs – symmetric, bilaterall

CT

Uneven ventilation; tapering of bronchi

CT

Collapse/ consolidation RUL, LUL; patient tachypneic

Consistent with JIA – lungs & bones

Biologic Therapy• Started azenil – immunomodulator

• 5.09 – age 2.3 yrs – Humira (anti TNF)

• Still active disease – respiratory & joints

• 12.09 – Remicade → allergic reaction

• 2.10 – age 3 yrs – Mabthera (B cell depletion)

• Still recurrent resp. exacerbations; inflammatory markers ↑

• 6.10 – age 3.3 yrs – Anakinra (kineret – anti IL-1)

• Improved on therapy; joint & resp. exacerbation when stopped → gradual improvement on cont. therapy

CXR – 10.8.10

Points for Discussion

• Severe JIA, started at early age; reluctant to

therapy

• Pulmonary disease –

Severe respiratory infection at age 50d → severe

obstructive disease

Post-infectious (adenovirus?) BO?

Presenting symptom of JIA??

• Severe, chronic lung disease related to JIA

• Several biological therapies – further pul. insult?

• …Eventual improvement – joint & respiratory –

despite/ due to biological therapy?

Pulmonary complications of JIA• Systemic JIA – arthritis, prolonged fever PLUS rash,

serositis, generalized lymphadenopathy, HSM

• Pulmonary involvement in JIA – rare, mainly

polyarticular/ systemic JIA; significant pul.

manifestations (except pleuritis) – rare, exclude

other causes (infection, SLE, vasculitis) (Kendig 8th

edition, 2012)

• Pleuritis & pericarditis have been described

• PAH, ILD, alveolar proteinosis, lipoid pneumonia –

rare (Kimura et al., Arthritis Care Res 2013)

• Pulmonary disease may be the presenting symptom

– immune dysregulation precedes systemic

inflammation

cont.-Pulmonary complications of JIA

• ILD – 8% in RA, 1-14% in juvenile SLE (Nisar et al., Paed Resp Rev 2013)

• Case reports – BO in a patient with JIA receiving gold (Pegg at al., Rheumatol 1994); BO in JIA presenting as pneumomediastinum (Dikensoy et al., Respiration 2002)

• A single case report of pulmonary capillaritiesleading to alveolar hemorrhage (Watanabe et al., Rheumatol Int 2012)

• Even in asymptomatic patients – PFTs – reduction of FVC, PEF, Pi max, Pe max; DLCO

• Inverse correlation to RF, ESR, disease duration, Mtx duration (Alkady et al., Rheumatol Int 2012)

Pulmonary complications of JIA -clinical

• Kimura et al., Arthritis Care Res 2013:

• 25 patients with systemic JIA and PAH, ILD and/ or

alveolar proteinosis compared to controls (JIA

without pul. disease)

• Patients – more females; more systemic features;

more exposure to IL-1 inhibitors, steroids, IvIG,

cyclosporine, cyclophosphamide

• 17 patients (68%) – on biologic therapy at onset of

pul. symptoms

• Bad prognosis – 17 (68%) died, mean 10.2 months

from diagnosis of pul. complications

Pulmonary complications of JIA - clinical

(Kimura et al., Arthritis Care Res 2013)

Pulmonary complications of biologic therapy

• In recent years – advances in biological therapies for rheumatic diseases

• bDMARDS – biologic disease-modifying anti-rheumatic drugs

• Specific targeting of the immune system

• Change in prognosis of patients BUT – concern of pul. side effects/ aggravating lung disease

• Studies performed in adults; not enough pediatric data

• ILD – under/misdiagnosed; mild disease –subclinical; attributed to infection/ underlying disease; post-marketing reports provide most information

Biologic therapies for inflammatory arthritis

(Nisar et al., Paed Resp Rev 2013)

Pulmonary Complications - Mtx

• In adults – severe side effects in long term use have

been described

Pulmonary toxicity – 2-7% in low dose

Acute hypersensitivity pneumonitis – most severe

Pulmonary fibrosis (Provenzano et al., Rheumatol 2003)

• May have a synergistic effect with biological therapy

• Leiskau et al., Clin Exp Rheumatol 2012:

68 patients with JIA, Mtx for median 6.7 yrs

After 3 yrs - ↓ MMEF, DLCO; no clinically relevant

lung disease

No correlation to Mtx dose/ JIA type

Pulmonary complications – anti TNF

• The first recombinant protein used for rheumatic diseases

• Long term post-marketing surveillance data –acceptable safety profile

• In theory could benefit RA-associated ILD

TNF involved in pul. fibrosis

Animal studies – anti TNF abrogates bleomycininduced pul. fibrosis

• BUT – TNF blockage → cell lysis, proteolyticenzymes from macrophages → epithelial injury → fibrotic cascade (Nisar et al., Paed Resp Rev 2013)

Pulmonary complications – anti TNF –cont.

• Infection – clinical trials – higher rate of URTI,

esp. first 3 months of therapy

• BSRBR – British Rheumatology register – X 2

serious infections; number needed to harm – 59

• JIA - ↑ serious infections compared to placebo (Nisar at al., Paed Resp Rev 2013)

• Cochrane 2013 – no increase in serious adverse

events/ serious infections (combined all group of

biologics for RA)

Pulmonary complications – anti TNF –cont.

• TB activation – TNF-α – critical in the immune response to TB

• Anti TNF – reactivation of latent infection

• Screening for latent TB – mandatory before Tx!

• ILD – first described in 2002Mainly enbrel for RA

38% - pre-existing ILD, worsened after biologic therapy

63% - current/ previous Mtx use

Poor prognosis

No reported cases in children (Nisar et al., Paed RespRev 2013)

Pulmonary complications – B cell depletion (mabthera)

• Targets all stages of B cell maturation

• Used in RA and hematological malignancies

• Uncontrolled trials in JIA

• Resp. symptoms – 38% - cough, bronchospasm, dyspnea, sinusitis, rhinitis; 10% - RTI

• Onset from Tx until resp. symptoms/ radiological abnormalities – 30d (0-158d)

• 69% - full recovery (Tx stop & steroids)

• ILD – rare – 0.01-0.03% in adults

• Bad prognosis – 19% died

• No reports of ILD in children (Nisar et al., Paed RespRev 2013)

Pulmonary complications – anti IL-6

• Licensed for JIA in Europe & USA

• Most common adverse events – diarrhea and

pneumonia

• No reactivation of latent TB

• In adults – 12 new onset non-infectious pul.

complications – 3 culture neg. pneumonia, 6

lung toxicity, 3 ILD

• No reports of ILD in JIA (Nisar et al., Paed Resp Rev

2013)

Pulmonary complications – anti IL-1

• IL-1 – pro-inflammatory – key in development of

sJIA

• Anakinra – proposed as first-line steroid sparing

in JIA; approved for RA

• ↑ risk of infections (also sJIA); 7 reports of ILD in

RA patients

• Pediatric – 1 report of pul. fibrosis in long term

Tx (Rilonacept) (Nisar et al., Paed Resp Rev 2013)

JIA Pul. manifestations

Pleuritis & pericarditisPAH, ILD, alveolar

proteinosisPFTs ↓ - correlated

with disease activity

Pulmonary damage

Mtx

Anti TNF

Anti IL-1

Anti IL-6B cell

depletion

InfectionsTB activation

ILD

Pulmonary improvement?

…Back to our patient

• 30.1.14 – age 7yrs:

• Treated with anakinra X 1/wk; azenil; iron & vit. D

• Fully active, no respiratory or joint complaints

• PE – lungs – few crepitations (rt.); no active

arthritis; residual limitation – neck, rt. ankle, wrists

(mild)

• PFTs – FVC 50%, FEV1 56%, FEF 25-75 67%

CXR

CXR – 24.2.13