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RHEUMATOLOGY UPDATE
2011
Richard Keating, MD, FACR, FACP
Program Director, Rheumatology Fellowship
Professor of Medicine
Section of Rheumatology
October 8, 2011
CRITERIA FOR REVIEW
Interest to a broad IM audience
Major insight into pathogenesis or understanding
of a common disease
Immediate potential to change clinical practice
Topics from across the spectrum of
rheumatology practice
2010-2011 time frame
GOUT
An Old Treatment
Revisited
Arthritis & Rheumatism 2011;63:412-421
BACKGROUND
• Gout is an inflammatory arthritis induced by
deposition of MSU crystals in synovial fluid and
tissues
• Humans lack uricase – can’t convert urate to
soluble allantoin as the end product of purine
metabolism
• Risk factors include age, diuretics, metabolic
syndrome, HF, HTN, and organ transplantation
• Over 6 million in US have gout
NEJM 2011;364:443
BACKGROUND
• Gout follows hyperuricemia – defined as a SUA
>6 mg/dl
• Anti-hyperuricemic Rx is recommended in
setting of tophi, recurrent attacks, and
nephrolithiasis – not isolated hyperuricemia
• Allopurinol is the most commonly used urate
lowering Rx and is quite effective in decreasing
tophi and flares but only when one achieves &
maintains a SUA <6 mg/dl
NEJM 2011;364:443
BACKGROUND
• Most treated with allopurinol receive 300 mg/day
allopurinol or less without reaching goal of SUA
<6 mg/dl
• Mild rash develops in ~ 2% of patients
• Severe allopurinol hypersensitivity syndrome
(AHS) less common but can be life-threatening
Arthritis & Rheumatism 2011;63:412-421
BACKGROUND
• AHS is feared in setting of renal impairment …
• Relationship between oxypurinol concentration
and AHS remains unproven
• There really is no direct evidence of need to
lower dose in renal impairment to decrease risk
of AHS
Arthritis & Rheumatism 2011;63:412-421
AJM 1984;76:47-56
AJM 1984;76:47-56
METHODS
• 83 patients with gout on stable dose allopurinol
for 1 month – no azathioprine
• 45/83 were not at SUA goal of < 6 mg/dl
• “Recommended” dose of allopurinol was
increased by 50-100 mg each month until target
SUA of <6 mg/dl was achieved
• Seen monthly until target SUA stable for 3 visits
and then seen q3 month until 1 year
Arthritis & Rheumatism 2011;63:412-421
Arthritis & Rheumatism 2011;63:412-421
Arthritis & Rheumatism 2011;63:412-421
Arthritis & Rheumatism 2011;63:412-421
RESULTS
• 35/45 in whom dose increased completed 12
mos study
– 3 rashes (2 concomitant admin furosemide)
– 4 lost to follow-up
– 3 intervening, non-related medical problems
• 31/35 (88.8%) achieved goal SUA without
problems at 1 year visit
– R+ 50 (5) - R + 150 (6) - R + 300 (2)
– R+ 100 (15) - R + 200 (6) - R + 400 (1)
• Mean time to achieve goal was 3.9 months
Arthritis & Rheumatism 2011;63:412-421
RESULTS
• 18/45 (40%)in escalation group were on
furosemide
• 13/18 receiving furosemide completed one year
of study
– 2 developed rash
– 3 intervening medical problems, unrelated
• Those on furosemide were just as likely to
achieve goal
Arthritis & Rheumatism 2011;63:412-421
TAKE HOME MESSAGE
• Convincing evidence of a relationship between
allopurinol hypersensitivity and renal impairment is
lacking
• Most patients can achieve goal SUA with dose
escalation without side effects if allopurinol is titrated
carefully
• Can & should escalate allopurinol dosing, even in renal
impairment, to a target SUA of <6 mg/dl
• Compliance is key to successful gout management
Arthritis & Rheumatism 2011;63:412-421
Arthritis & Rheumatism 2011;63:412-421
RHEUMATOID
ARTHRITIS
New Criteria
Arthritis & Rheumatism 2010;62:2569-2581
BACKGROUND
• RA is a chronic inflammatory autoimmune
disease characterized by joint inflammation and
destruction, early death and disability
• Pre-clinical autoimmunity in the form of
rheumatoid factor (RF) and anti-citrullinated
protein antibody (CCP) can precede clinical
disease
• DMARDs (MTX) and biologics have dramatically
changed RA management – but early
employment is key to successful disease control
Arthritis & Rheumatism 2010;62:2569-2581
BACKGROUND
• Classification (not diagnosis) of RA has been
based on the1987 ACR criteria; developed in
patients with well established RA
• 1987 criteria demonstrated poor sensitivity for
early disease
• Diagnosis of early disease is necessary for early
intervention and a better outcome
• 2010 ACR/EULAR criteria were developed with
purpose of facilitating early recognition of RA
Arthritis & Rheumatism 2010;62:2569-2581
1987 CLASSIFICATION CRITERIA
Reminder: RA is a clinical diagnosis and
ACR Criteria are for study entry criteria …
Arthritis & Rheumatism 2010;62:2569-2581
COMMENTARY
• Synovitis is required – arthralgia alone is
not adequate
• Symmetry is not a feature
• Not diagnostic criteria - an attempt to
discriminate among patients with synovitis
who will evolve into RA
Arthritis & Rheumatism 2010;62:2569-2581
TAKE HOME MESSAGE
• New criteria avoids classifying RA by late
manifestations – when therapy too late to
be effective
• 2010 criteria focus on early inflammatory
features that predict evolution to RA
• Classification criteria are used for clinical
trial eligibility – not diagnosis – and will
foster early treatment clinical trials
Arthritis & Rheumatism 2010;62:2569-2581
RHEUMATOID
ARTHRITIS
Pathogenesis Insight
Ann Rheum Dis 2011;70:508-511
ANTIBODIES TO CITRULLINATED PROTEINS
(anti-CCP)
Arginine residues are modified to citrulline by PAD at sites of
inflammation
Antibodies to citrullinated proteins (anti-CCP) are
relatively specific to RA
Van Boekel et al. Arthritis and Research Therapy 2002;4:87
1. Arginine (A) on peptides is converted to citrulline by the enzyme PAD
in setting of local inflammation
2. Peptides are processed by APCs
3. APCs with shared epitope MHC molecules bind citrulline with high affinity
and present citrullinated self Ag to T-cells
4. T-cell activation by the APC s leads to clonal expansion of T-cells and CMI
against citrullinated antigens
5. B-cells reactive to citrullinated peptides are activated by T-cells, causing
production of anti-CCP antibodies
Niewold TB, et al. QJM 2007;100:193
ANTI-CCP & RA
• RA is a “new” disease in the Old World and
tracks with introduction of sugar and
attendant periodontal disease to Europe
– Gingival bacteria (P. gingivalis) make PADI and RA
patients have increased periodontal disease …
• RA is strongly associated with smoking
– Smoking induces peptide deimination which leads to
increased risk of developing anti-CCP antibodies …
RA GENETICS
• Estimated that the SE alleles account for at least
30% of the total heritability in RA
• There are likely other, still unidentified, risk alleles
within the MHC region
• Large advance in past 5-10 years in identification
of risk alleles outside the MHC – but these
alleles contribute far less than MHC alleles to
RA heritability (3-5% of genetic burden vs.
30% for SE)
Raychaudhuri, Nat Genet 2008;40:1156
ADDITIONAL RA RISK ALLELES
Plenge, Curr Opin Rheumatol 2009;21:262
METHODS
• Swedish cohort of 1205 RA patients / 872
controls
• Genotype, antibody, and smoking hx
• Estimate the relative risk of RA conferred by
different amoutns of smoking in the context of
different HLA-DRB1 genotypes to estimate the
excess fraction of RA cases attributable to
smoking
Ann Rheum Dis 2011;70:508-511
RESULTS
• 61% of RA patients CCP (+)
• No association between smoking, SE alleles, and CCP (–)
patients
• For CCP (+) patients, the excess fraction of cases
attributable to smoking was 35% (higher in men than
women)
• Among CCP (+) patients with double SE alleles, the
excess fraction of cases attributable to smoking was 55%
Ann Rheum Dis 2011;70:508-511
Ann Rheum Dis 2011;70:508-511
TAKE HOME MESSAGE
• The environmental-genetic link, so elusive
in most autoimmune diseases, is coming
into focus in RA
• Smoking is an essential risk factor for RA
• Strongly discourage smoking in a person
with a family history of RA
Ann Rheum Dis 2011;70:508-511
NSAIDs
Primum Non Nocere
BMJ 2011;342:c7086
BACKGROUND
• All COX-2 inhibitors confer an increased CV risk
– Rofecoxib (COX-2) withdrawn from market in 2004 in
light of CV events
• Debate has surrounded CV safety of NS-COX vs COX-2
– Several meta-analyses were unable to answer
question on safety
• Network meta-analysis allows a unified, coherent
analysis of all randomized controlled trials that compare
NSAIDs head to head or to placebo
BMJ 2011;342:c7086
METHODS
• All large scale RCT comparing any NSAID with other
NSAID or placebo
• 31 trials / 116,429 patients / 117,218 patient years of f/u
• At least 100 person-years of follow-up in the studied
arms
• High methodological quality of trials
• Primary outcome was MI / Secondary outcomes
included CVA, death from CVD, and death from any
cause
BMJ 2011;342:c7086
BMJ 2011;342:c7086
RESULTS
• Safety profiles of individual drugs varied
considerably depending on the outcome
(MI, CVA, CV death, death any cause)
• The estimated rate ratios for
comparisons with placebo were
generally imprecise with low numbers of
events for most outcomes
• All NSAIDs have CV risk, not just COX-2
• Naproxen has the least harmful CV
safety profile – but remember GI toxicity
BMJ 2011;342:c7086
COMMENTARY
• Meloxicam and valdecoxib not included
• Regimens were from trials, not clinical practice – where
intermittent usage is more common
• Number of events for most outcomes was low, but keep
in mind that these are trials and very controlled
• Intermittent use vs chronic use
• Network meta-analysis uses indirect comparisons which
requires several assumptions about homogeneity of
populations studied
BMJ 2011;342:c7086
TAKE HOME MESSAGE
– COX-2 inhibitors, especially at high doses, should be
avoided in patients at high risk for CV disease
– Most studied of the NS-COX are diclofenac,
ibuprofen, and naproxen
• Diclofenac has the worst CV profile
• Ibuprofen had the highest risk of CVA and interferes with
ASA prophylaxis
– Naproxen probably has the best CV safety profile
of all NSAIDs, but this needs to be weighed
against GI toxicity
BMJ 2011;342:c7086
VASCULITIS
New Treatment …
Something to RAVE About ?
NEJM 2010;363:221-232
BACKGROUND
• Most patients with WG or MPA have
antineutrophil cytoplasmic antibodies
(ANCA) against proteinase 3 or MPO
• ANCA associated vasculitis (AAV) affects
medium to small sized vessels with a
predilection for lung and kidney
NEJM 2010;363:221-232
J Am Soc Nephrol 2010;21:745-752
BACKGROUND
• CTX and corticosteroids have been the mainstay
of Rx for AAV for 40 years
• CTX and corticosteroids are effective, but
fraught with long term side effects
• Remission is common, so is relapse
• AAV is associated with B-cell activation and
rituximab effectively depletes peripheral B cells
NEJM 2010;363:221-232
METHODS
• 197 ANCA (+) patients with either WG or MPA
• Multicenter, noninferiority, randomized, double-blind,
double-dummy trial
• ANCA (+) / active disease / new dx or relapse / no
ventilator or creatinine >4 mg/dl
• RTX (375 mg per meter squared for 4 weeks) c/w CTX
(2 mg/kg per day) with concomitant glucocorticoid taper
• Primary end point was remission without use of
prednisone at 6 months
RAVE – Rituximab in ANCA-Associated Vasculitis Trial NEJM 2010;363:221-232
RESULTS
• Comparable numbers of RTX-based regimen reached
the primary end-point compared with the CTX-based
regimen (.64 vs .53)
• RTX-based regimen was more efficacious than CTX-
based regimen for inducing remission of relapsing
disease (.67 vs .42)
• RTX was as effective as CTX in the treatment of patients
with major renal disease or alveolar hemorrhage
• There were no significant differences between treatment
groups with respect to adverse events.
RAVE – Rituximab in ANCA-Associated Vasculitis Trial NEJM 2010;363:221-232
RESULTS
• No differences between CTX and RTX groups in numbers of total
AE, SAE, or non-disease related AEs
• More patients in CTX group than in RTX group had or or more of the
pre-defined selected adverse events (.33 vs .22)
• Initial 6 mos - 1 solid malignancy / 2 deaths in CTX group and 1
solid malignancy / 1 death in RTX group
• After 6 mos – 6 malignancies in 5 additional patients
– 4 in RTX group (pap thyroid CA, uterine CA, prostate CA, colon CA x 2,
bladder CA, lung CA)
– 1 in CTX group (prostate CA, lung CA)
• With exception of 2 prostate cancers, all cancers developed in
patients who had exposure to at least 2 medications known to
increase CA risk (CTX, MTX, AZA)
RAVE – Rituximab in ANCA-Associated Vasculitis Trial NEJM 2010;363:221-232
TAKE HOME MESSAGE
• RTX plus glucocorticoids provides similar results to CTX
plus glucocorticoids for the treatment of AAV
• A higher percentage of RTX treated patients reached the
primary end point (.64 vs .53) – clearly not inferior
• Those with relapsing disease may be better served by
RTX than CTX
• Retreatment with RTX ?
RAVE – Rituximab in ANCA-Associated Vasculitis Trial NEJM 2010;363:221-232
SLE
A New Treatment
Lancet 2011;377:721-731
BACKGROUND
• As of 2010, the only FDA approved drugs for
lupus were:
– Aspirin
– Hydroxychloroquine sulfate (Plaquenil)
– Prednisolone
– Triamcinolone hexacetonide (Kenalog)
• Belimumab (Benlysta) was approved by the
FDA in 2011 for “adult patients with active,
autoantibody positive SLE who are receiving
standard therapy”.
Lancet 2011;377:721-731
BELIMUMAB
• Belimumab is a human IgG1 gamma ab that
binds to soluble (not transmembrane) B-
lymphocyte stimulator (BLyS) – a key survival
factor for B lymphs
• Most commonly involved organ systems at
enrollment were MSK, mucocutaneous, and
hematologic
• Not studied or approved for CNS or renal
• As effective in AAs – unclear?
Lancet 2011;377:721-731
BELIMUMAB
• Safety:
– No increase in serious infections
– Depression more common with belimumab
– Mild infusion reactions
• Cost:
– One year of therapy will cost 35,000 USD
• Administration:
– 10 mg/kg IV q 2 weeks for 3 doses and then monthly
Lancet 2011;377:721-731
TAKE HOME MESSAGE
• 1ST new medication approved for SLE in 50
years
• Appropriate patients are seropositive with active
MSK and cutaneous disease
• Not studied and not recommended for LN or
CNS lupus
Lancet 2011;377:721-731
WEGENER’S
GRANULOMATOSIS
What’s in a Name ??
Arthritis & Rheumatism 2011;63:863-864
GRANULOMATOSIS WITH POLYANGIITIS
(WEGENER’S)
• Friedrich Wegener was an early and ardent supporter of the
National Socialist Party - the eponymous title of WG honors
his work from the 1930s
• Suspicion he was involved in selection of Jews for genocide
• Detained as a suspected war criminal by Allies in 1945, but
never tried and no strong evidence that he was involved in
human experimentation
• American College of Chest Physicians (ACCP) awarded
Wegener a “master clinician” prize in 1989 but rescinded the
same in 2000 after his Nazi past recognized
• Journals and societies (ACR, EULAR, ASN) are making an
effort to rename the condition Granulomatosis with
Polyangiitis (GPA) and retire the eponym
Arthritis & Rheumatism 2011;63:863-864
rkeating@medicine.bsd.uchicago.edu
