Disclosure statement Relapsing

 Collaborative research agreement with Polychondritis Novo Nordisk

Jane Hoyt Buckner, MD Benaroya Research Institute Virginia Mason Medical Center Seattle WA

11/6/2011 Jane Hoyt Buckner 1

Topics of Discussion What is RP?

Relapsing Polychondritis is an inflammatory disease of the hyaline cartilage  Spectrum of disease in RP Hallmarks of the disease- inflammation of cartilage  Diagnosis involving:  Pathogenic mechanisms of disease • Auricular •  Management Nasal • Costochondral  Case Studies • Respiratory Tract • Joints

Lahmer et al Autoimmunity Reviews (2010) 540–546

What is RP? Beyond Chrondritis Diagnostic Criteria

Inflammation of structural component of end Clinical Manifestations organs: McAdam’s Criteria Bilateral auriclar chondritis require: 3 clinical Nonerosive, seronegative inflammatory polyarthritis manifestations, Nasal chondritis • Ocular with biopsy Ocular inflammation • Vasculopathy confirmation unless the Respiratory tract chondritis • Vasculitis diagnosis is Cochlear and /or vestibular dysfunction • Nephritis clinically obvious. Pathology • Encephalitis Cartilage biopsy with histologic findings compatible with relapsing polychondritis.

Ref. Medicine 55:193, 1976

Lahmer et al Autoimmunity Reviews (2010) 540–546

Relapsing Polychondritis 1 Epidemiology Auricular Chondritis  Frequency in the population

 Over 550 cases reported  Inflammation of the external ear is the most common manifestation of  3.5 cases/million (Rochester, Minnesota) RP  Age  83% of patients

 mean at onset 40-50  Erythema, tenderness and swelling  Ranging from 16-90 present for days-weeks

 Gender  Sparing of the ear lobe is typically  F:M=1:1 found

BRI RP registry  Thickening and or drooping of ear  14 patients/3 million King County lobe may result from a flare of RP.  178 patients participating from the United States.

Auricular Chondritis Clinical Manifestations

Audiovestibular Symptoms: Differential diagnosis • Cellulitis . Tinnitus, • Dermatitis . vertigo • Trauma . hearing loss. • Frostbite Outcome: • Infectious perichondritis (TB,syphilis, leprosy, fungal) . Hearing loss in 30% • Chondrodermatitis nodularis . Vestibular dysfunction in >15%

Nasal Chondritis Nasal Chondritis Epidemiology: Differential Diagnosis  38% have symptoms at dx  Trauma  48% will develop symptoms  Infectious (Syphilis, TB, leprosy, Symptoms: fungal) Tenderness Erythema  Granulomatous diseases Epistaxis  Wegener’s

Findings:  Midline Granuloma • Erythema/ tenderness over the bridge of  Lymphomatoid granulomatosis the nose. • Saddlenose deformity  Hereditary chondropathy • Septal perforations Testing  Check ANCA an all patients  Consider CT of sinuses

Relapsing Polychondritis 2 Large Airway Involvement Large Airway Involvement Epidemiology: Assessment of Disease:

21% of patients have respiratory  Pulmonary function testing involvement  flow volume loops 70% are female  Direct visualization 54% airway involvement is first RP manifestation  Larygoscopy  bronchoscopy Tracheomalacia and mixed air trapping pattern in patient with relapsing polychondritis. Symptoms (in patients with airway  CT scanning- (a) Transverse end-inspiratory CT scan of trachea shows normal results. involvement): (b) Transverse dynamic expiratory CT scan at a similar level demonstrates  Calcification of trachea excessive collapse of the trachea, which is consistent with tracheomalacia. • Dyspnea- 64%  Dynamic expiratory CT will show • Cough Outcome: tracheal collapse and air trapping • Hoarseness •Tracheomalacia/Tracheal collapse - • Stridor 48%  PET Scan • Wheezing •Subglottic stenosis-26% •Focal stenosis of the bronchial tree Causes of airway obstruction: • edema, inflammation • fibrous infiltration and obstruction • Destruction of cartilage CHEST 2009; 135:1024–1030

Large Airway Involvement Vascular Complications

Differential Diagnosis: • Trauma Pathology • Tramatic intubation . Cutaneous vasculitis • Sarcoid . Medium or Large vessel vasculitis • Wegener’s granulomatosis

Assessment: Treatment: • Tracheostomy  Echo cardiogram • Laser therapy  EKG • Balloon dilitation  angiogram • Airway stenting

Vascular Complications Ocular Complications Episcleritis

 Episcleritis, scleritis

Treatment  Iridocyclitis

1) Medical treatment  Optic neuritis 2) Aortic valve replacement  Retinopathy 3) Aneurysm repair  Proptosis, lid edema Outcome Scleritis . Scleromalacia

Relapsing Polychondritis 3 Clinical Manifestations Clinical Manifestations

Renal Arthritis Symptoms: • Microhematuria, • Proteinuria . Arthralgia • elevated creatinine . Oligo and polyarticular arthritis • hypertension . Costochondritis  Biopsy: Outcome: • segmental necrotizing . Nondestructive arthritis glomerulonephritis with crescent formation,

Clinical Manifestations Associated Disorders

CNS Rheumatic Other

• encephalitis Systemic Vasculitides Myelodysplasia • meningoencephalitis Rheumatoid Arthritis Lymphoma Sjogren’s Syndrome Leukemia • myelitis • polyneuritis Systemic Lupus Pernicious Anemia • cerebellar signs Behcet’s Disease Myasthenia Gravis Spondyloarthropathies Primary Biliary Cirrhosis Scleroderma Mixed Cryoglobulinemia Wegener’s Thyroid disease

Pathologic Findings Pathogenic Mechanisms

Immunologic role in RP  Cellular infiltrates in the 1) Pathologic findings of inflammation. perichondrial tissues. 2) Response to immunosuppressive therapy 3) HLA associations  Degeneration of the marginal chondrocytes and depletion of 4) Animal models of chondritis matrix proteoglycans. 5) In vitro evidence responses against cartilage antigens in patients.  Deposition of IgG and C3 at the chondrofibrous junction.

Relapsing Polychondritis 4 Animal Models of RP Pathogenic Mechanisms Evidence of Humoral Immunity in RP

Animal Agent Features Reference  Histologic evidence of IgG deposition in the Rat Type II Auricular chondritis, Cremer et. al. cartilage of patients. collagen Arthritis J. Exp. Med. 154;1981 (bovine)  Evidence of serum IgG binding to cartilage. HLA Type II Auricular chondritis, Bradley et. al.  Antibodies present against type II collagen. DQ6/8 collagen Destructive Arthritis J. Immunol. mice (bovine) 161; 1998  Antibodies detected against site specific Rat Matrilin-1 Tracheitis, Hansson et. antigens: type IX, XI collagen and matrilin-1. (bovine) Nasal chondritis al. J. Clin. Invest. 104; 1999

Management Medical Management Identify organ involvement Steroid sparing agents: • Pulmonary compromise NSAIDs • Assess Hearing . MTX Prednisone • Renal . Leflunomide • Vascular involvement Dapsone . Azathioprine Disease Activity Colchicine . Cyclophosphamide • Physical exam . Cyclosporine • Markers of inflammation

Medical Management Next Steps

 Biologics Development of diagnostic tests. .Anti-TNFa therapies  Autoantibodies .Abatacept now under study  T cell specificities. .Rituximab Develop markers of disease activity. .Tocolizumab anti-IL-6  Immunologic parameters  Measurement of cartilage breakdown Autologous BMT products.

Relapsing Polychondritis 5 78 yo male with RP

 Patient who presented at age 48 with  Auricular chondritis, deformity of the ears  Nasal chondritis (development of saddle nose)  Chostochondritis  Hoarseness and SOB ( tracheo-bronchiomalacia)  Vertigo  Anti CII Ab + intermittently CASE STUDIES IN RP  Biopsy equivocal

 Co-morbidities = CLL

78 yo male with 50 yo male with RP

 Patient who presented at age 43 with  Complications :  Auricular chondritis, bilateral and recurrent  post-obstructive pneumonia  Intermittent ocular inflammation (episcleritis)  Stent placement- requiring removal  Anti CII Ab -  Medications:  Biopsy not done

 Prednisone for 24 years ( now 5-10 mg daily)  Family hx + parent with RA

 Dapsone x 2 yrs nor impact  Initial response to Prednisone, taper failed  MTX 15mg weekly for 20 years.  MTX failure  Etanercept no in remission x 5 years 30 years post diagnosis stable with significant respiratory compromise, steroid related morbidity No complications or co-morbidities

59 yo male with RP 66 yo female with RP  Patient who presented at age 48 with  Auricular chondritis ( resulting in floppy ears)  Patient who presented at age 42 with  Vertigo/ hearing loss ESR- nl  Auricular chondritis, bilateral intermitteny  Episcleritis CRP- elevated  Nasal chondritis ANC-neg  Later developed Anti-CIIab neg  Episcleritis (responsive to topical steroids)  Hoarseness (tracheal narrowing) Anti- CCP-neg  Anti CII Ab +  Nephritis with proteinuria RF-neg  Biopsy not diagnostic Treated with cytoxan- with resolution of both  On steroids to control disease flares (5-10 mg over 12 years)  Destructive arthritis After referral to my clinic:  Chronic pain and fatigue Responsive to steroids >20mg daily  Pt started on MTX- stopped due to hair loss Not responsive to : anti-TNFa drugs/ rituximab/abatacept/ rituximab/  Leflunamide started- tolerated no flairs off Prednisone >3 years. tocilizumab- currently with normalization of CRP  PFT, ECHO, CXR all normal no comorbidities. Co-morbidity- osteoporosis/ depression

Relapsing Polychondritis 6 61 yo female with Wegener’s 61 yo female with Wegener’s granulomatosis granulomatosis

 Patient who presented at age 15 with a saddle nose deformity  Patient who presented at age 52 to my clinic with new bilateral  Age 21 (1971) she presented with hemoptysis, pulmonary auricular chondritis. infiltrates, sinus congestion and glomerular nephritis.  Recurrent nephritis.

 Wegener’s was diagnosed and the patient was treated with  Conjunctivis and corneal ulcer. cytoxan and Prednisone followed by azathioprine.  Age 30 the patient devleoped subglottic stenosis requiring Diagnosis: Wegener’s Granulomatosis with RP overlap. tracheostomy and cytoxan therapy was given again Patient has been relatively stable for >8 years with  1995 the patient had laser surgery to open her airway, and the tracheostomy was no longer required. Close follow-up of renal function and ANCA Patient is unwilling to have her tracheostomy site closed.  1998 pt was found to be p- ANCA + and Hep C + (presumed from a tansfusion in 1971) Treatment: MMF + low dose prednisone Will consider using rituximab if her disease flairs.

ELISA for IgG antibodies to collagens in RP patients and controls

2.00 1.75 1.50 1.25 1.00 0.75

mean O.D. mean 0.50 0.25 0.00 -0.25 HI CII BII HII

.Antibodies to HII in 52% of the RP patients tested and 4.5%.normal controls.

Pathogenic Mechanisms Management Cellular Responses to Cartilage Identify organ involvement Antigen Subject Prolif. SI>3 IL-2 IFN-g Combined • Pulmonary compromise Type II RP 10/37 (37%) 1/7 (14%) 5/10 (50%) 12/27 (44%) • Hearing loss Collagen Normal 5/26 (19%) ND 0/10 5/26 (19%) • Vestibular dysfunction Cartilage RP 12/31 (39%) 6/16 (35%) 7/20 (35%) 19/31 (61%) • Renal/vascular involvement Extract Normal 8/37 (22%) ND 0/37 8/37 (22%) Disease Activity • Physical exam IFN-g is produced in response to cartilage antigens in patients with • Markers of inflammation RP, but not by normal controls.

Relapsing Polychondritis 7 Medical Management Next Steps

Development of diagnostic tests.  NSAIDs Potential therapies  Autoantibodies  Prednisone .Leflunomide   Steroid sparing agents: .Anti-TNFa therapies T cell specificities.

. MTX Develop markers of disease activity. . Azathioprine  Immunologic parameters . Cyclophosphamide  Measurement of cartilage breakdown . Cyclosporine products.

Col2CTx Assay Next Steps

1000

500 500  Identify individuals with this disease for

400 systematic study of:

ng/ml 300  Development of diagnostic tests 200  Determinants of clinical outcome 100  Predictors of disease activity 0  Identification of genetic factors Controls OA RA RP

Measurement of type II collagen degradation product via Inhibition ELISA assay. The difference between control values and each disease state is significant with p<0.01.

Goals of Research in RP Clinical Manifestations of RP

 Chondritis  Improve our understanding of the  Auricular mechanisms of disease, in order to  Nasal choose appropriate therapies  Laryngotracheal  Use of cytokine specific therapies  Audiovestibular dysfunction  Inhibition of cartilage destruction  Arthritis  Development of tolerance to  Ocular inflammation autoantigens  Vasculitis  CNS

 Renal

Relapsing Polychondritis 8 Treatment of Complications of RP

 Airway obstruction and collapse:  Tracheostomy  Laser therapy  Airway stenting

 Aortic root dilitation  Aortic valve replacement  Aneurysm repair

Relapsing Polychondritis 9