Spondy Treatment

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Nice review article from Medscape.

Return to Medscape coverage of: <A

HREF= " http://www.medscape.com/viewprogram/530 " >American College of Rheumatology

64th Annual

Scientific Meeting </A>

Treatment Advances in the Spondyloarthropathies

J. Cush, MD   <A

HREF= " http://www.medscape.com/viewprogram/530_authors " >Disclosures</A>

Introduction

The spondyloarthropathies are a group of rheumatic disorders that includes

ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, and

enteropathic arthritis. These disorders are unified in their ability to

manifest axial and/or peripheral inflammatory disease with the associated

features of enthesitis (inflammation at tendinous attachments to bone),

ocular inflammation, skin and nail changes, and mucosal lesions affecting the

gastrointestinal tract or genitourinary tracts. These diseases may be

difficult to diagnose and often manifest features overlapping with the other

conditions listed, and thus are often collectively referred to as

spondyloarthropathies. Numerous reports addressing these disorders can be

summarized under the following categories: advances in treatment; diagnostic

modalities/diagnostic features; and disease pathogenesis.

Advances in Treatment

The spondyloarthropathies are uncommon disorders affecting fewer than 1

million Americans. Thus, the low number of patients with these diseases has

limited drug development by the pharmaceutical industry for these disorders.

Therapies proven to be effective in other inflammatory disorders (ie,

rheumatoid arthritis) are often tried in the spondyloarthropathies, which are

characteristically inflammatory in nature. Thus, nonsteroidal

anti-inflammatory drugs (NSAIDs) commonly have been the mainstay of therapy

for most patients with ankylosing spondylitis, Reiter's syndrome, psoriatic

arthritis, or enteropathic arthritis.[1]

Moreover, several disease-modifying antirheumatic drugs (DMARDs) such as

sulfasalazine, methotrexate, azathioprine, cyclosporine, and gold have been

suggested to be effective in some patients with chronic progressive disease.

Unfortunately, only sulfasalazine has been well studied in these disorders

and the remaining agents have been reported in limited, uncontrolled

studies.[2,3] Sulfasalazine has been shown to be most effective in those

patients with peripheral synovitis (eg, psoriatic arthritis and Reiter's

syndrome) and least effective in those with pure axial inflammation (eg,

ankylosing spondylitis). These treatment options are only partially effective

in some and are often associated with significant toxicities. Thus, the need

for more effective and tolerable therapies for the spondyloarthropathies has

been perceived by many for years.

Numerous reports have demonstrated the efficacy and safety of the recently

released tumor necrosis factor (TNF) inhibitors -- etanercept and infliximab

-- in spondyloarthropathy patients. The TNF inhibitors appear to be

exceptionally effective and well tolerated in patients with both axial and

peripheral inflammatory arthritis. The rationale for the use of these agents

stems from the research of Emery and colleagues,[4] who have shown that the

primary pathology underlying the spondyloarthropathies is enthesitis and that

enthesopathy can explain many of the articular and axial manifestations of

these disorders.

There is some controversy, however, regarding TNF-alpha promoter allele

frequencies in ankylosing spondylitis. TNF mRNA has been identified from the

sacroiliac joints of patients with ankylosing spondylitis. However, studies

of genetically manipulated animals that overexpress and overproduce TNF-alpha

have shown a propensity for the development of enthesitis.[4] Thus, it

appears that TNF may play an important role in the initiation or perpetuation

of enthesitis. For these reasons, the following researchers have presented

their early results on the effectiveness of TNF inhibitors in this setting.

Mease and coworkers[5] recently published their experience with etanercept in

60 patients with psoriatic arthritis. Open-label treatment data from the

earlier 12-week study were also presented.[6] Of the original 60 patients, 58

continued with open-label therapy. The same level of clinical response was

observed in the joints and skin. At 9 months, 28% had no tender joints, 42%

had no swollen joints, and 40% had a disability score of zero. Many of these

patients were able to either reduce (43%) or discontinue (25%) their dose of

concomitant methotrexate.

Similar results were seen by Dechant and colleagues,[7] who treated 10

psoriatic arthritis patients in an open-label trial with infliximab (5 mg/kg

at weeks 0 [baseline], 2, and 6 with lower doses of 3-4 mg/kg once weekly for

more than 8 weeks thereafter). All patients had polyarticular disease and 7

of 10 patients were also receiving methotrexate therapy. Half of these

patients achieved an ACR70 response rate that was prolonged in many.

Cessation of infliximab therapy was associated with prolonged responses, and

2 patients flared 6-9 months after discontinuation of infliximab. One patient

withdrew from the study because of infusion reaction and pregnancy. After 1

year, 6 of 9 patients had no swollen or tender joints.

Several studies showed the efficacy of etanercept and infliximab in patients

with ankylosing spondylitis.[8,9] Gorman and colleagues[8] studied 16

patients with ankylosing spondylitis who continued to receive background

NSAIDs and DMARDs and were randomized to receive etanercept 25 mg

subcutaneously twice weekly or placebo for 4 months. These patients showed

dramatic improvement in morning stiffness, spinal pain, patient global

assessment, swollen joints, and the Bath Ankylosing Spondylitis Functional

Index (BASFI). Brandt and colleagues[9] studied 11 patients with ankylosing

spondylitis in an open-label uncontrolled study of infliximab (5 mg/kg

intravenously at weeks 0, 2, and 6), and marked improvement (> 50%) occurred

in 10 of 11 patients, with improved quality of life scores (as measured by

SF-36 and BASFI) and improved inflammatory activity measured by the Bath

Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein

(CRP).

Stone and coworkers[10] from Toronto reported on their open-label experience

with infliximab in 22 patients with ankylosing spondylitis who exhibited

active disease by BASDAI and had failed conventional therapies. All patients

had sacroiliitis and tested positive for HLA-B27. Two patients had primarily

axial disease, 4 patients had peripheral disease alone, and the remaining 16

patients exhibited both axial and peripheral arthritis. Patients were treated

with infliximab 5 mg/kg at weeks 0, 2, and 6 and then once weekly for 8 weeks

thereafter. Patients remained on stable NSAID, DMARD (5 patients were

receiving methotrexate </= 15 mg/wk), and prednisone throughout the study.

Outcomes were impressive, with reductions in BASDAI score, erythrocyte

sedimentation rate, and CRP levels. The only adverse effects noted were

headache and upper respiratory infection in 1 patient each. Patients can be

divided into 2 groups by treatment response: those who had dramatic and

immediate response, which was the majority of patients (group A), and those

with a slower but still favorable (albeit less dramatic) response (group .

Group B patients had longer disease durations (14.7 vs 7.5 years), worse

functional measures of ankylosing spondylitis (ie, chest expansion, Schober

test), and greater degrees of spinal ankylosis when compared with group A.

MRI studies were performed on 8 patients and showed resolution of

inflammatory synovitis or sacroiliitis as early as 2 days postinfusion. Three

patients with uveitis responded well to treatment and 1 patient later

relapsed.

Similar findings of clinical efficacy were also seen in studies of patients

diagnosed with a spondyloarthropathy other than ankylosing spondylitis, often

with marked improvement in pain scores, activity scores (BASDAI), and

functional scores (BASFI).[11,12]

Many studies have shown favorable open-label responses to TNF inhibition in

patients with the spondyloarthropathies. It is currently not known whether

such therapies will be able to change the natural course of disease or if

they will have differential clinical efficacy on axial disease, peripheral

disease, and extra-articular disease (eg, uveitis).

Ocular Manifestations of Rheumatic Diseases

T. Rosenbaum, MD, from the Oregon Health Sciences University[13]

presented some of the ocular manifestations and presentations of uveitis

associated with the spondyloarthropathies.

Uveitis refers to inflammation of the uveal tract -- the midportion of the

eye, which includes the iris, ciliary body, and choroids layer. Inflammation

of any of these may occur in uveitis and may individually be referred to as

iritis, iridocyclitis, or choroiditis. Uveitis is associated with a systemic

disease in 20% to 40% of patients. Iritis (anterior uveitis) is easily

identified by the ophthalmologist using slit lamp examination. The aqueous

humor is normally clear, but in inflammation it has a higher protein content

and many inflammatory cells which causes a " haze " or disruption of light as

it passes through the exudative aqueous humor. Similar to the diagnosis of

various forms of arthritis, the diagnosis of uveitis can be made by

historical features (eg, onset), physical findings (anterior vs posterior

uveitis), and response to therapy. Anterior uveitis commonly occurs in the

spondyloarthropathies and sarcoiditis. Posterior uveitis (choroiditis or

retinitis) is commonly associated with infection, sarcoidosis, and Behçet's

disease. Bilateral uveitis occurs in pauciarticular juvenile rheumatoid

arthritis in about 50% of cases, while psoriatic arthritis is the cause of

uveitis in about 5% of cases.

Features seen in uveitis (but not specific to uveitis) include corneal edema,

keratitis precipitates, band keratopathy, and posterior synechiae. Band

keratopathy is caused by calcific deposits (usually at 3 and 9 o'clock) that

may extend across the cornea to impair vision. Posterior synechiae are

fibrous adhesions between the iris and lens and lead to a scarred,

irregularly shaped pupil.

The numerous causes of uveitis include:

Infectious -- cytomegalovirus, herpes simplex virus, mycobacterial,

tuberculosis, Lyme disease, toxoplasmosis, histoplasmosis

Immune-mediated -- ankylosing spondylitis, Reiter's syndrome, psoriatic

arthritis, Crohn's disease, sarcoidosis, Behçet's disease, Sjögren's

syndrome, multiple sclerosis, interstitial nephritis (NSAID-induced), Cogan's

syndrome (uveitis or interstitial keratitis, cranial nerve VIII vasculitis),

lupus, Kawasaki's disease

Syndromes confined to the eye -- pars planitis

Masquerade syndromes -- leukemia, lymphoma, retinitis

Anterior uveitis may present as a painful, acute " red eye. " Often the pupil

is small due to spasm of the ciliary muscles. The erythema is mostly located

about the limbus. A high percentage of men with sudden onset of anterior

uveitis will have a systemic disease, usually a spondyloarthropathy. Patients

with a spondyloarthropathy and uveitis outnumber inflammatory bowl disease

(IBD)-associated anterior uveitis by almost 10:1. Such patients will have an

acute onset of unilateral red eyes, pain, and photophobia. These features

contrasts with those seen in children with pauciarticular JRA, who have a

painless, insidious onset and more chronic course. Half of the IBD patients

with uveitis will have an acute/sudden onset, most are female (88%), nearly

two thirds are bilateral, and posterior uveitis with vitreal inflammation is

far more likely with IBD than with a spondyloarthropathy. Uveitis associated

with psoriatic arthritis is as common as IBD-associated uveitis, such that

nearly 7% of all psoriasis patients may develop uveitis. It tends to be

insidious, bilateral, posterior in location, and usually HLA-B27-negative.

Other studies have shown that HLA-B27 positivity is an independent risk

factor for both axial disease (ie, sacroiliitis, spondylitis) and uveitis. In

contrast, sarcoidosis is another common cause of uveitis, and as such,

uveitis is the second most common presenting manifestation of sarcoidosis.

Sarcoidosis may present with anterior and/or posterior uveitis, retinal

vasculitis, or conjunctivitis.

Disease Pathogenesis

Two basic hypotheses underlying the pathogenesis of the spondyloarthropathies

were questioned by 2 studies.[14,15] Both the role of CD8+ T cells and

molecular mimicry were addressed.

The pathogenesis of the spondyloarthropathies was questioned by a group

studying the role of CD8+ T cells. Taurog and colleagues[14] presented their

work on the depletion of CD8+ T cells in HLA-B27-positive transgenic rats.

Previously it had been suggested by many researchers in this area that

recognition of an unknown antigen or peptide (presented in the context of the

class I MHC molecule HLA-B27) by CD8+ T cells was a necessary step in the

pathogenesis of these diseases. These views stemmed from the well-known

association between class I MHC molecules and CD8+ T cells and anecdotal

reports of HIV+ patients with either psoriasis or Reiter's syndrome having

more aggressive disease, thereby suggesting the relative lack of importance

for CD4+ T cells in disease pathogenesis. In Taurog's animal model,[15]

HLA-B27 transgenic rats develop gut inflammation, arthritis, and other

features of spondyloarthropathy. Rats were depleted of CD8+ T cells by

treatment with an anti-CD8 monoclonal antibody and subsequent thymectomy.

Such interventions had no effect on the clinical outcomes, thereby

questioning the importance of CD8+ T cells in the pathogenesis of the

spondyloarthropathies.

Implications for Clinical Practice

Many of these reports represent the earliest work in the field and will

continue to refine understanding of the spondyloarthropathies and how they

should be treated. Advances in the pathogenesis of these disorders have

already shown that TNF inhibition may be effective in the control of axial

and peripheral inflammatory disease. Based on these reports, the use of TNF

inhibitors in psoriatic arthritis and ankylosing spondylitis is becoming more

widespread and thus offers more options to those patients not adequately

managed with conventional therapies (eg, NSAIDs, sulfasalazine). Some

investigators have claimed the TNF inhibitors to be more effective in the

spondyloarthropathies than in rheumatoid arthritis. Nonetheless, further

controlled studies are needed.References

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