2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH...

52
2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH Associate Professor of Medicine Division of Rheumatology and Clinical Immunology Rheumatology Section Chief Birmingham VA Medical Center American College of Physicians Alabama & Mississippi Chapters Scientific Meeting Point Clear, AL 2017

Transcript of 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH...

Page 1: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH

Associate Professor of Medicine Division of Rheumatology and Clinical Immunology

Rheumatology Section Chief Birmingham VA Medical Center

American College of Physicians

Alabama & Mississippi Chapters Scientific Meeting Point Clear, AL

2017

Page 2: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

DISCLOSURES

• Consultant fees from SOBI pharmaceuticals

Page 3: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

EVIDENCE BASE SLIDE

• Arthritis & Rheumatology 2016; 68: 1828-1838, 27 JUL 2016

• Arthritis & Rheumatism Vol. 54: January 2006, pp 38–46

• Ann Rheum Dis 2016;75:2060-2067

• Ann Rheum Dis 2016;75:1824-1830

• Arthritis & Rheumatology. Vol. 69; 2017, pp 926

• Lancet 2016; 387: 1921

• International Journal of Rheumatology Volume 2013, Article ID 912562

• Abstract 911. American College of Rheumatology Conference Proceedings.

• Ann Rheum Dis 2016;0:1–14.

• Arthritis Care & Research Vol. 64, No. 10, October 2012, pp 1431–1446

• Ann Intern Med. 2017;166:58-68.

Page 4: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

RHEUMATOLOGY UPDATE

Sources:

• My own experience and what I like • Highlights from American College of Rheumatology 2017

meeting • Journal clubs with pizza • Recommendations from UAB faculty

Page 5: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

ROADMAP

• Pre-disease • New treatment for an old disease • A new disease • A controversy

Page 6: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

CASE PRESENTATION 1: PRE-DISEASE

• A 40 year-old man presents for a well-check visit • Tells you that his older sister has been recently diagnosed with

rheumatoid arthritis • There also is a history of RA in his father and grandparents • He does not have any symptoms or physical findings • He is afraid about RA and asks for advice about what to do

Page 7: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

You suggest: A. He needs to lose weight B. He needs to have comprehensive

genetic testing C. He should strongly consider

stopping smoking D. He should go into an antioxidant

diet E. He should start taking

methotrexate Response Counter

Page 8: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

Arthritis & Rheumatology 2016 68: 779-788,

WHAT IS EARLY DISEASE?

Phases of RA development

Page 9: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

Genetic Susceptibility to RA

• Heritability ~ 50% for seropositive RA

• Familial aggregation (risk of RA in 1st degree relatives increased 3 fold)

• Concordance rates of 15-30% between monozygotic twins

• Concordance rates of 5% in dizygotic twins

• >100 genetic susceptibility loci associated with RA

Mother

Daughter Frisell T,et al. Arthritis Rheum2013;65:2773–82. Okada Y, et al. Nature 2014;506:376–81. Slide courtesy of Maio Danila, MD MsPH

Page 10: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

Associations of Smoking and Age With Inflammatory Joint Signs Among Unaffected First‐Degree Relatives of Rheumatoid Arthritis Patients: Results From Studies of the Etiology of Rheumatoid

Arthritis

Arthritis & Rheumatology 2016; 68: 1828-1838, 27 JUL 2016

Page 11: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

RELATIVE RISK RA IN CCP+ SUBJECTS EXPOSED TO SMOKING AND HLA–DR (SE) GENES

ARTHRITIS & RHEUMATISM Vol. 54: January 2006, pp 38–46

Page 12: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

MODERN IMAGING TECHNIQUES

Musculoskeletal ultrasound Magnetic resonance imaging

Shapiro L and Gold G. Hochberg at al (eds) Rheumatology 5th ed, 2011

Wakefield RJ and O’Connor P. Hochberg at al (eds) Rheumatology 5th ed, 2011

Page 13: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

DEVELOPMENT OF CLINICAL SYNOVITIS IN ASYMPTOMATIC CCP+ PATIENTS

Jackie L Nam et al. Ann Rheum Dis 2016;75:2060-2067

• PD: Musculoskeletal ultrasound power Doppler score

Page 14: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

DEVELOPMENT OF CLINICAL ARTHRITIS IN PATIENTS WITH ARTHRALGIAS ACCORDING TO MRI-DETECTED INFLAMMATION

Hanna W van Steenbergen et al. Ann Rheum Dis 2016;75:1824-1830

Page 15: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

OPPORTUNITIES FOR INTERVENTION: METHOTREXATE TREATMENT IN HIGH RISK UNDIFFERENTIATED ARTHRITIS PATIENTS

Burgers LE et al. Arthritis & Rheumatology. Vol. 69; 2017, pp 926

Plus 2 ongoing trials with abatacept and rituximab…..

Page 16: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

CONCLUSIONS

• Immune dysregulation and inflammation occur pre-clinically in RA (and possibly other autoimmune diseases)

• Initial insult may occur in locations other than the joint (lung, mucosae)

• Cohorts of individuals at risk, CCP antibodies, advanced imaging are providing valuable information

• Early intervention and modification of natural history is a realistic goal

Page 17: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

CASE PRESENTATION 2: NEW TREATMENT FOR AN OLD DISEASE

• 74 year old white woman develops headache, blurry vision, diplopia, and fever

• Past medical history remarkable for type 2 diabetes and osteoporosis

• Sedimentation rate is 82 • She is started on 1 mg/kg of prednisone

Page 18: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

BIOPSY SPECIMEN OF THE LEFT SUPERFICIAL TEMPORAL ARTERY AND THE DURA.

Brass SD et al. N Engl J Med 2008;359:2267-2278.

Page 19: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

Which cytokine is known to drive the inflammatory process in this condition: A. TNFα B. IL-1 C. IL-6 D. TGF-β E. VEGF

Response Counter

Page 20: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

CLINICAL SPECTRUM OF GIANT CELL ARTERITIS

GCA/PMR Syndrome

Polymyalgia Rheumatica • Pain & stiffness in shoulder and pelvic girdles

Cranial arteritis •Headache, optic ischemia, jaw claudication

Cachexia/wasting syndrome •Fever, night sweats, weight loss, depression

Large vessel vasculitis/aortitis •Limb claudication, pulse discrepancy, aortic insufficiency and aneurysms

Page 21: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

COMMON CLINICAL FEATURES GIANT CELL ARTERITIS

• Headache • Increased sensitivity of the

scalp • Pulsating, enlarged, or

nodular temporal artery • Jaw claudication • Less common: Trismus, facial

pain, tongue claudication or infarction, carotidynea, visual or auditory hallucinations

Page 22: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

GCA: TREATMENT PARADIGM AND CHALLENGES

• Glucocorticoids in high doses Hyperglycemia, mood alterations, sleep disruption

• Glucocorticoid taper • Frequent relapses No effective glucocorticoid sparing agents

• Chronic long term glucocorticoids Osteoporosis, infections, depression

Page 23: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

GCA AND INTERLEUKIN 6

Control PMR GCA

Roche N. Arthritis Rheumatol. 1993; 36: 1286

Page 24: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

TOCILIZUMAB IN GCA

• IL6 receptor antagonist

• Open label, phase II A: Relapse free survival B: Time to taper off prednisone

Lancet 2016; 387:1921

Page 25: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

TOCILIZUMAB IN GIANT CELL ARTERITIS TRIAL

Unizony S. International Journal of Rheumatology Volume 2013, Article ID 912562

Page 26: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

EFFICACY AND SAFETY OF TOCILIZUMAB IN PATIENTS WITH GIANT CELL ARTERITIS: PRIMARY AND SECONDARY OUTCOMES FROM A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Short course prednisone

(n=50)

Long course prednisone

(n=51)

Weekly Tocilizumab

(N=100)

Every other week Tocilizumab

(n=49)

Sustained remission at 52 weeks, n (%)

7 (14) 9 (17.6) 56 (100) 26 (53.1)

Cumulative prednisone dose, mg

3296 3817 1862 1862

Withdrawals due to adverse events, n (%)

2 (4.0) 0 7 (7.0) 3 (6.1)

Serious adverse events, n (%)

11 (22.0) 13 (25.5) 15 (15.0) 7 (14.3)

Infection serious adverse events, n (%)

2 (4.0) 6 (11.8) 7 (7.0) 2 (4.1)

Stone JH. 2016 ACR Conference. Abstract 911

Page 27: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

GIACTA TRIAL: TOCILIZUMAB VERSUS PREDNISONE

• Weekly tocilizumab versus short-term prednisone: Sustained remission difference 42.0 % (18-66) p < 0.0001

• Weekly tocilizumab versus long-term prednisone: Sustained remission difference 38.4 % (17.9-58.8) p < 0.0001

Stone JH. 2016 ACR Conference. Abstract 911

Page 28: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

CONCLUSIONS

• Interleukin 6 plays a role in the pathophysiology of giant cell arteritis

• Interleukin 6 inhibition is a promising approach for inducing remission, symptom control, and minimizing glucocorticoid exposure

Page 29: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...
Page 30: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

CASE PRESENTATION 3: A NEW DISEASE

• 56 year old man • Presents after a year of weight loss, enlargement of

submandibular salivary glands, lower extremity swelling, increased creatinine

• Biopsy of submandibular gland is non-diagnostic: “benign” “fibrosis”

Page 31: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...
Page 32: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

Which laboratory abnormality is more likely: A. Elevated levels of SSA (Ro)

antibody B. Positive titers for anti-nuclear

antibodies C. Elevated levels of IgG4 D. Monoclonal lymphocyte

population in flow cytometry E. Peripheral eosinophilia and

elevated IgE levels Response Counter

Page 33: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

IgG4-RELATED DISEASE: YOU MAY HAVE SEEN IT BEFORE

FIBROSING MEDIASTINITIS Clinical Imaging 39 (2015): 993

MICULIZ‘S DISEASE Arch Soc Esp Oftalmol. 2014;89:332

RIEDEL’S THYROIDITIS Endocrinol Metab (Seoul). 2013; 28: 138

RETROPERITONEAL FIBROSIS AND AUTOIMMUNE PANCREATITIS ACG Case Rep J. 2017; 4: e7.

PRIMARY SCLEROSING CHOLANGITIS World J Gastroenterol. 2014; 20: 3245

Page 34: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

IgG4-RELATED DISEASE

• Fibro-inflammatory condition of unknown etiology • Multiorgan: likely integrates multiple single organ diseases • Unexplained swelling, infiltration, or enlargement of one (40%

of cases) or more organs • Indolent presentation: weight loss (21%), asthenia (26%),

fever uncommon (8%)

Page 35: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

IgG4RD: ORGAN SPECIFIC SYMPTOMS Organ syndrome Differential diagnosis or prior single-organ

diagnosis

Salivary gland enlargement (42%), lymphadenopathy (42%), Lacrimal gland swelling (26%)

• Mikulicz syndrome • Sjogren’s syndrome • Orbital pseudotumors, lymphoma, Tolosa-

Hunt, sarcoidosis

Jaundice (23%), pruritus, abdominal discomfort, hepatomegaly (6%)

• Autoimmune pancreatitis • Sclerosing cholangitis

Renal dysfunction, lower extremity swelling, low back pain

• Retroperitoneal fibrosis • Membranous glomerulopathy

Aortitis • GCA • Takayasu’s • Syphilis

Headache, ophtalmoplegia. pachymeningitis • CNS vasculitis • Granulomatosis with polyangiitis

Neck pain and enlargement • Riedel’s thyroiditis

Dyspnea, pulmonary nodules, ground glass opacities, bronchial thickening

• Interstitial lung disease • Fibrosing mediatinitis

Page 36: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

IgG4-RD: PATHOGENIC MECHANISMS

• Genetic factors: increased

susceptibility among Asians • Unknown trigger: molecular mimicry

and bacterial infections • Autoimmunity: induced by IgG4 and

other antibodies • Inflammation: induced by cell

infiltration, eosinophilia, and increased IgE production

• IgG4 antibodies play an unclear role: pathogenic? Destructive? Protective?

Stone JH et al. N Engl J Med 2012;366:539-551.

Page 37: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

IgG4RD: COMMON LABORATORY FEATURES

Laboratory abnormalities Frequency (%) Serum IgG4 > 135 mg/dL 84 Serum IgG levels > 1800 mg/dL 61

Serum IgE > 360 IU mL 58 Eosinophilia 34 Elevated C-reactive protein 18 Autoantibodies • Anti-nuclear • Rheumatoid factor • SSA

32 20 6

Low complements 36

• IgG4 neither sensitive nor specific

• Wide laboratory variability

• IgG4 prozone

• Flow cytometry: Increased circulating plasmablasts (CD19 low CD38+ CD20- CD27+)

Adapted from Mayo Clin Proc. 2015;90(7):927-939

Page 38: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

IgG4-RD: HISTOPATHOLOGICAL FEATURES Storiform fibrosis Obliterative phebitis

Positive immunostain for IgG4 plasma cells: • IgG4+ cells per high-power field >10 • IgG4+/total IgG+ cell ratio >40%

Annu. Rev. Pathol. Mech. Dis. 2014.9:315-347

Page 39: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

IgG4-RD: TREATMENT APPROACH

• Initial good responses to glucocorticoids (prednisone equivalent at 0.5-0.6 mg/kg/day)

• Methotrexate, azathioprine, mycophenolate unproved steroid sparing agents

• Good experience with rituximab, likely by depleting plasmablast precursors

Page 40: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

CONCLUSIONS

• IgG4RD is a fibro-inflammatory disease of unknown origin which causes tumefaction in ≥ 1 organ

• Laboratory features are supportive but not diagnostic • Diagnosis is best established by histopathological features • Glucocorticoids and rituximab are the best proven treatment

approaches

Page 41: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

CASE PRESENTATION 4: A CONTROVERSY

• A 52 year old man was diagnosed with gout 4 months ago, after recurrent episodes of podagra

• No tophi, normal kidney function • First serum urate is 10.2 mg/dL • Started on 100 daily mg of allopurinol, increased to 300 mg • Last flare was 3 months ago • On current visit serum urate is 7.0 mg/dL

Page 42: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

What should be done with his allopurinol?

A. Serum urate is still too high, it should be increased

B. No attacks have happened recently, it should be continued at the same dose

C. Allopurinol dose is already maximized, allopurinol should be changed to febuxostat

D. Allopurinol dose is already maximized, probenecid should be added Response

Counter

Page 43: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

BASIC CONCEPTS IN GOUT

• Painful inflammatory arthritis caused by the deposition of monosodium urate in tissues

• Treatment is aimed at decreasing flares and other symptoms (tophi, quality of life)

• Urate lowering therapies (e.g; allopurinol) are the mainstay of treatment

• Quality of care in gout is uniformly poor

Page 44: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

TREAT TO TARGET VS. TREAT TO SYMPTOMS

• American College of Rheumatology and European treatment guidelines recommend:

A serum urate treatment goal of 6mg/dL or less in patients without tophi

5 mg/dL or less in patients with tophi or joint damage

• This is called a treat to target (T2T) approach

Page 45: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

BIOCHEMICAL/PHYSIOLOGICAL EVIDENCE

• Soluble monosodium urate precipitates as monosodium urate crystals (MSU) past its saturation point

• Such saturation point at 37 oC is 6.8 mg/dL

Page 46: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

EVOLUTION OF HYPERURICEMIA AND GOUT

Asymptomatic Hyperuricemia

Acute Flares Advanced Gout

Painless Intercritical Segments

Painful Intercritical

Segments

Pain

Time

Over time, untreated, chronic hyperuricemia increases body urate stores, advancing the severity of the disease

Flares last longer

Flares occur more often

Intercritical segments decrease

Persistent pain and stiffness

Adapted from Klippel et al, eds. In: Primer on the Rheumatic Diseases. 12th ed. Arthritis Foundation; 2001:313.

Page 47: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

SMALL AMOUNT OF CLINICAL EVIDENCE FOR T2T- Lowering Serum Urate Decreases Acute Flares

• 86% (71/81) of patients who had serum urate <6.0 mg/dL did not experience an acute flare during the study period

Average serum urate during the whole investigation period, mg/dL

Inci

denc

e of

recu

rren

t gou

ty

atta

cks

mor

e th

an 1

yea

r af

ter e

ach

patie

nt v

isit,

%

Shoji et al. Arthritis Care Res. 2004;51:321-325.

5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 0.0

10.0

20.0 30.0

40.0

50.0 60.0

70.0

80.0

90.0

100.0

Observed Logistic regression

Page 48: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

LOWERING SERUM URATE DECREASES TOPHI SIZE

The lower the serum urate, the faster the velocity of tophi reduction

63 patients followed for a mean of 5 years Perez-Ruiz et al. Arthritis Rheum. 2002;47:356-360.

0 0.5 1 1.5 2 2.5 0

2

4

6

8

Seru

m u

rate

, mg/

dL

Velocity of reduction, mm/month

Allopurinol Benzbromarone Combined

Page 49: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

ACP RELEASES GOUT MANAGEMENT GUIDELINES

• ACP recommends “treatment to avoid symptoms (T2aS)”

• Limited evidence for T2T versus risk of medication escalation or repeated monitoring of serum urate

• View of serum urate as a surrogate for a clinical endpoint (like LDL, blood pressure, blood sugar)

Page 50: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

MY CONCLUSIONS

• T2T is supported by decades of clinical experience and (true) limited evidence

• Serum urate is more than a surrogate for gout, is a causative factor for the disease

• ACP guidelines could impair gout care in the US • But: ACP has exposed an important need for gathering

evidence supporting T2T strategies

Page 51: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

SUMMARY: 2017 RHEUMATOLOGY UPDATE

• Pre disease: Significant progress in rheumatoid arthritis pre-clinical and early disease

• New treatment for an old disease: IL-6 inhibition effective for GCA

• New disease: recognition and characterization of IgG4RD • A controversy: goals for gout treatment

Page 52: 2017 RHEUMATOLOGY UPDATE - Internal Medicine · 2017 RHEUMATOLOGY UPDATE Angelo L. Gaffo, MD MsPH ... IgG4-RELATED DISEASE • Fibro-inflammatory condition of unknown etiology ...

THANKS!