Re: DMARD

[Guest guest]

I'm sorry this is so long, but I believe it is important for everyone in our

group to read. I copied and saved the contents of the web site without adding

the link. I just tried to find it without success, so decided to sent it on to

you. I included the entire contents...so you could see the credentials of the

people involved. If you notice, this report was done by people in the UK.

Much of the current research for our disease has been done in the UK and many of

the current biologics were approved there before they were in the US. This

report is mostly on AS, psoriasis and Crohn's disease, but as we know, many

people with Reiter's (or ReA), go on to a DX of Ankylosing Spondylitis and

sometimes they are misdiagnosis in the beginning of the disease....to find out

later,

they have AS.

HELENA MARZO-ORTEGA, MRCP,

Research Fellow;

PAUL EMERY, MA, MD, FRCP,

Professor of Rheumatology and Lead Clinician,

Rheumatology and Rehabilitation Research Unit, The University of Leeds, 36

Clarendon Road, Leeds, LS2 9NZ, UK;

DENNIS McGONAGLE, MRCPI,

Senior Lecturer and Honorary Consultant Rheumatologist,

Rheumatology and Rehabilitation Research Unit, The University of Leeds;

Calderdale Royal Hospital, Salterhebble, Halifax HX3 0PW, UK.

Professor Emery is an Arthritis Research Campaign Professor of Rheumatology.

Dr. McGonagle's work is funded by the Medical Research Council of the UK.

The concept of disease modification was first introduced in rheumatoid

arthritis (RA) and refers to the ability of the so-called disease modifying

antirheumatic drugs (DMARD) to affect the underlying disease process and prevent

joint

damage. Traditionally, the term DMARD has been applied to various drugs that

have a modest or moderate effect on synovitis suppression and bone damage

retardation. However, the advent of powerful biologic agents such as infliximab

and etanercept has confirmed a long held view in RA — that is, providing

synovitis is adequately suppressed over time, then bone damage is minimal. By

contrast, a different scenario has applied in ankylosing spondylitis (AS) and

the

related spondyloarthropathies (SpA), where disease modifying effects of drugs

have yet to be defined. In recognition of this, investigators have chosen

terminology carefully and use terms such as " symptom modifying drugs " or

" disease

controlling antirheumatic therapy " (DCART). This article reviews the basis for

this discrepancy between RA and SpA and proposes that in the light of recent

advances in imaging and therapeutics in SpA, the concept of disease modification

may now be applied to these diseases.

Disease pathogenesis differs between RA and SpA. For example, in RA,

cartilage and bone destruction secondary to synovitis within small synovial

joints is

the primary disease outcome and it correlates with loss of function. Bone

damage is measured by conventional radiography, a well validated tool in RA, and

its prevention is the desired treatment goal. In contrast, AS and the SpA have

a predilection for the spine and large synovial joints, where prominent

reparative processes with bone sclerosis and new bone formation usually occur in

addition to bone destruction. These reparative bone changes are responsible for

joint ankylosis and cause disability in these patients. So, ideally it is not

the measurement of progressive radiographic destruction, but rather the failure

to develop ankylosis and bone deformities, that would represent true disease

modification in AS. However, it is at these sites, particularly at the spine,

where conventional radiography, the traditional imaging method used in SpA,

suffers from a number of limitations. First, radiography lacks the sensitivity

to show small focal changes in skeletal calcium content in large joints.

Second, the development of radiographic bone damage may be slow in AS, taking up

to

at least a decade to manifest. These factors have hampered the development of

the concept of disease modification in AS and SpA.

Table 1.Differences of disease pathogenesis between RA and SpA.

RAAS and SpA

PathologySynovitisEnthesitis, osteitis, and synovitis

Target tissueSynoviumEntheses, bone, and ?synovium

Affected sitesSynovial jointsSpine and large synovial joints

OutcomeJoint erosions, cartilage lossNew bone formation, erosion, and

cartilage loss

Outcome measures

Radiography Detects bone erosions withinDetects sclerosis, proliferative

new bone

2 years of disease in 80% of patientsformation, which in the spine can take

up to 10 years from disease onset

MRISynovitis primary, focal periarticularDiffuse bone edema at entheseal

sites primary.

bone erosion secondarySynovitis secondary?

However, there have been two advances in rheumatology in the last decade that

should allow for this to be developed. These are (1) the increasing use of

magnetic resonance imaging (MRI), and (2) the advent of new therapies that

suppress inflammation in SpA. Fat suppression MRI techniques are excellent for

showing sacroiliitis, enthesitis, and osteitis, which are the characteristic

primary spinal lesions in AS and which are also common within and adjacent to

synovial joints. Biologic antiinflammatory agents such as infliximab or

etanercept

were first proven to be highly effective in RA, and it is now emerging that

they are also efficacious in AS and all subtypes of SpA. Indeed, evidence so far

suggests that their efficacy in controlling signs and symptoms in patients

with chronic AS, psoriatic arthritis, and the SpA of Crohn's is comparable if

not superior to RA, suggesting a central role for proinflammatory cytokines such

as tumor necrosis factor-a (TNF-a) in the pathogenesis of these diseases. Our

own experience with etanercept suggests that this drug is very efficacious in

suppressing axial and peripheral joint disease even in established cases that

have proven resistant to conventional therapies. We have shown using MRI that

the primary lesion in the spine, enthesitis and osteitis, neither of which

were apparent on radiography, either completely regressed or improved after

treatment, and this was accompanied by major improvements in clinical and

laboratory measures of disease activity, including a fall in the acute phase

response

as measured by the C-reactive protein. These data confirm that different

anatomical regions of inflammation and not just synovitis respond to anti-TNF

therapy. Similarly, other investigators have recently used MRI to monitor the

efficacy of other biologics such as infliximab and other novel agents and have

reported similar findings.

Although MRI identifies a clear pathology occurring at the bone marrow and

related enthesis as well as the synovial joints, there are still a number of

unresolved issues. First, the relationship between inflammation and bone damage

in AS is not fully defined and the question remains: is there a linear

relationship between inflammation in AS and other SpA and subsequent joint

ankylosis?

The original histological studies by Bywaters suggested that bone ankylosis

may be independent of the associated inflammation, although these observations

were based on a limited number of histological sections. Also, experimental

models of AS and in particular the ANKENT mouse have prominent joint fusion

without much discernible inflammation. It is noteworthy, too, that diffuse

idiopathic skeletal hyperostosis (DISH), a disease that can sometimes resemble

AS, is

not regarded as having an inflammatory component. Even though enthesitis is

regarded as the primary pathological abnormality in SpA, definitive proof of the

relationship between enthesitis and osteitis and bone ankylosis is still

lacking. However, recent MRI and radiographic studies in early disease24

indicate

that MRI bone changes predate radiographic abnormalities, suggesting that in

AS, enthesitis and osteitis is primary and bone changes such as sclerosis or

syndesmophytes are secondary. Therefore, to demonstrate unequivocally that these

new drugs constitute true DMARD in SpA, it will be necessary to show that

sustained reversal of the inflammation at the enthesis and adjacent bone

prevents

subsequent radiological fusion of the joint and associated loss of function.

Evidence so far is reassuring, as studies conducted to date with biologic

agents have shown dramatic response, even when used to treat patients where a

degree of irreversible joint fusion had already occurred, suggesting that there

is

room for disease modification even at later stages. However, confirmation of

this can only be achieved by the systematic and controlled longitudinal

observation of large cohorts of patients. From a theoretical perspective,

inflammation generally hinders new bone formation and tends to favor the

development of

osteoporosis. It will therefore be important to carefully document that

suppression of inflammation at the spinal entheses is not associated with

increased

new bone formation with joint fusion and spinal ankylosis.

MRI is increasingly used as a research tool and should be able to address the

effects of other drugs in AS and SpA. Bisphosphonates have been shown to

cause regression of MRI determined osteitis, and could potentially have

modifying

properties in SpA; this awaits further MRI studies. Similarly, it is unclear

whether the excellent response noted to nonsteroidal antiinflammatory agents in

AS could be associated with regression of the enthesitis associated bone

pathologies. The ability to image the primary site of pathology with MRI may

also

facilitate the development and validation of biomarkers, which could be a

simpler way of assessing disease modification in SpA, as Maksymowych, et al have

demonstrated in their study.

There is now growing anatomical and therapeutic evidence to introduce the

concept of disease modification in SpA. This is based on the fact that new and

more potent antiinflammatory agents are emerging and that sensitive imaging

techniques such as MRI can be used to measure regression of inflammation at the

different sites of disease. Confirmation that suppression of MRI determined

osteitis prevents subsequent bone ankylosis could herald a new era for the

appraisal of therapies in SpA, whereby drugs will be initiated based on the

evidence

for their effect at the primary site of disease in SpA rather than on a

successful track record in the therapy of RA, as has been the case until now.

REFERENCES

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sulphasalazine

alone in early rheumatoid arthritis. Lancet 1997;350:309-18.

3. Strand V, Lassere M, van der Heijde D, K, Boers M. Recent

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corticosteroids prevent progression of erosions in methotrexate treated early

RA. An

MRI/HRUS study [abstract]. Arthritis Rheum 1998;41 Suppl:S238.

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Suppl:S355.

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Characteristic magnetic resonance imaging entheseal changes of knee synovitis in

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rheumatoid

arthritis patients receiving concomitant methotrexate: a randomised phase III

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13. Brandt J, Haibel H, Cornely D, et al. Successful treatment of active

ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal

antibody infliximab. Arthritis Rheum 2000;43:1346-52

14. Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of

psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000;356:385-90.

15. Van den Bosch F, Kruithof E, de Vos M, et al. Crohn's disease associated

with spondyloarthropathy: effect of TNF-alpha blockade (infliximab) on the

articular symptoms. Lancet 2000;356:1821-2.

16. Marzo-Ortega H, McGonagle D, O'Connor P, Emery P. Efficacy of etanercept

in the entheseal pathology in spondyloarthropathy. Arthritis Rheum

2001;44:2112-7.

17. Stone M, Salonen D, Lax M, Payne U, Lapp V, Inman R. Clinical and imaging

correlates of response to treatment with infliximab in patients with

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amelioration of refractory peripheral spondyloarthritis by pulse intravenous

pamidronate therapy. J Rheumatol 2001;28:144-55.

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Spondyloarthropathies. London: Grune and Stratton; 1984:43-68.

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enthesopathy. Pathol Res Pract 1998;194:797-803.

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Glass D, editors. Oxford textbook of rheumatology. Oxford: Oxford University

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Rheumatol

1999;26:1953-8.

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[Guest guest]

In a short sentence...it has been proven that DMARD help early spondy disease

and that we shouldn't wait to use them until the damage is shown on

Xray....which can take up to 10 yrs. Since this article was published (from the

UK)

there have been many more reports from the USA saying the same thing. I knew

that

this was true of Ankylosing spondy...but it seems it is for ReA, too. More

and more Rheumatologists are beginning to treat all the spondy diseases earlier

with DMARD/TNF-a and other drugs besides just NSAID and pain killers. I sent

the full article so no one would think I was promoting or twisting the facts.

Sorry that some of the article was garbled in transmission. All the newer

clinical tests have shown that these drugs help spondy arthritis (especially the

TNF-a drugs) even more than they do Rheumatoid Arthritis. It's really what

several of us (Janet and others) have been saying for several months now. The

real

problem is the cost for those under 65yrs. I'm getting mine free. Humira has a

program for Medicare patients who do not have prescription drug coverage. I'm

sure that when the new Medicare plan comes into effect...they will get paid

then. :-) They feel they will get their money some day...and they are getting a

jump on the competition now. When my doctor told me of this, I couldn't

believe it. She submitted our request and I was approved. I've been on Humira

for

several months now...with great success regarding arthritis and pain. I've had

no side effects. I still have problems with uveitis. Hoping that eventually it

may help? My Rheumatologists will most likely drop my Methotrexate on my next

visit.

Best regards to you, Connie NC. I get reports of the ice and snow in

Asheville. I wish I could see it...must be beautiful. I'm one of those crazy's

that

love snow. Hey, don't give me too much credit with being " knowledgable " . I'm

just tired of so many years of hurting and don't want others to go through what

I've had to go through...when there is finally help available. We just have to

keep up with the new reports coming out

Connie (granny). PS. I started out going to write one sentence. I get carried

away!

[Guest guest]

Researchers are testing combination treatments for reactive arthritis. In

particular, they are testing the use of antibiotics in combination with TNF

inhibitors and with other immunosuppressant medicines, such as methotrexate and

sulfasalazine

http://www.niams.nih.gov/hi/topics/reactive/reactive.htm

[Guest guest]

Grannyof9, Great article. I read it and absorbed most of it, I think. But, I

know you are far more knowledgeable than I am about this disease and all the

medical descriptions. Can you translate to me what the report is saying. I think

this is what my doctor was talking about last visit. Please.

Connie NC

charlie1622@...

[Guest guest]

Thank you, Connie (granny). Yes, you are a lot more knowledgeable than a lot of

us. On my last visit to the Rheumy he took x-rays again. I get x-rays about

every two years. My Doctor made the comment that my x-rays looked

unremarkable(little bone damage or fusion) But I still have so much pain and

cannot walk without the Remicade. My doctor said, that at the last big

Rheumatologist Conference , all the Rheumys came to the same conclusion, AS acts

different in women than men, and they still do not know why. AS in women is

harder to detect and it takes a different course. He said they are trying to

find ways to detect and find AS in women earlier, before the disease goes on too

long before being detected. It seems to be a mystery to the Rheumys.

But one thing is for sure, my doctor is very much convinced that the Remicade

helps me tremendously, Thank the Lord. He has watched me go from limping and not

able to walk to being able to walk, go to the store , my limp went away. I still

hurt some, but only if I over do. When you feel better you tend to overdo, have

to pace yourself and watch yourself sometimes. I love the Remicade. I am on 10

bottles now, started with four.

One interesting note: my last infusion was last Friday and the nurse told me

that Remicade had sent out a memo to all the doctors that the cost of the

Remicade was going DOWN. It was $990.00 dollars per bottle and now it will be

$720.00 dollars per bottle. I thought that was strange. Drug companies do not

drop their prices unless the patent runs out. It has not run out on Remicade

yet. So, I wonder what the real deal is?? Does anyone have any theories. And the

Doctor told me that Remicade has proven to help Spondy people more than

Rheumatoid people. I just feel blessed to be able to get Remicade and my

Insurance has been very kind to pay for all of it. I wish we had some kind of

health care system where everyone could have the treatments they need. These

diseases are so hard on us, no one should have to suffer when help is out there.

Thanks again Connie(granny) for helping me to understand the article.I really

appreciate all the help I can get. I am so happy the Humira is working so good

for you. It makes a big difference in your quality of life, doesn't it.

Connie NC

charlie1622@...