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Facts And Future Outlook:
What can we expect will happen to us over the months and years ahead ? Statistical facts are as follows: There is the
"explosive" onset where RA can show it's ugly head in a matter of weeks,or even days.
The gradual type where a wrist becomes swollen and for some time it's the only problem. Or a patient develops marked
tenderness under the balls of both feet (MTP joints ),particularily when first getting up,first thing in the morning.
Gradually,over several weeks to several months,more and more joints join the picture. Fatigue and morning stiffness make
their appearance. It may take a year or so before the picture is clear enough for a definite diagnosis.
In 10 % of cases,RA starts off like gout. A single joint,such as the knee,wrist or shoulder,suddenly becomes very painful,swollen
and warm. Often the pain is so severe that the joint can't be used. Two or three days later,it's back to normal. After a month
or so,another attack strikes,usually in another joint.
As time goes by,the attacks become more frequent. Gradually they are less and less severe but more frequent.,ans instead
of clearing up,the swelling and pain start to persist. One day,perhaps after a year or more,it becomes obvious it is RA. This
pattern is called palindromic rheumatism,and while it doesn't always turn out to be RA,it most often does.
Palindromic rheumatism may clear up as mysteriously as it comes on,may continue indefinetly,or,may evolve into very active
RA,requiring aggressive action.
Very rarely,RA first appears in an "extra-articular" (non-joint ) site,with joint symptoms appearing months later. When
it does,it ususually takes the form of chest complications,and the patient is usually a male.
In people with mild RA (betwen 5-20 %),there is a spontaneous disappearance of symptoms,usually within the first
2 years. However,more than 50 % of those will have a recurrance of RA with various levels of severity.
Another 5 to 20 % have a more progressive course,leading to some deformity of joints.
The majority of people with RA undergo a pattern of persistent and progressive deterioration that aggressively destroys
cartilage and bone.
More than 80 % are partially disabled within 12 years after the diagnosis of the disease,and 16 % are completely disabled
Given the statistics,you should remember that the progression of RA often cannot be predicted in a given individual.
Predictions based on graphs,tables etc yield only numbers People with Ra are individuals,each with a unique set of genes,health
histories and unmeasureable reserves of physical strengths and weaknesses that defy inflaliable predictions.
At the same time we need to be realistic and admit that RA is usually a disease which can be slowed down,but a cure is
on the horizon. We may go into remission,but the disease usually returns if therapy is completely stopped.
Medications that once worked may become non-effective with passage of time. Medications that worked "wonders" for
some patients,will do nothing for others. Side effects that occurred in some patients that caused them to discontine the medication
may not happen in your case. Medication doseage will be different,etc.
We also know that promp diagnosis and early,aggressive treatment can go a long way in modifying the advance of RA. It
is never too late for treatment. This realiazation adds urgency to the efforts underway to understand RA more and
deal with it much more effectively.
The DMARDs commonly used in RA include hydroxychloroquine (HCQ), sulfasalazine (SSZ),methotrexate (MTX),leflunomide (Arava),etanercept
( Enbrel),and infliximab (Remicade ). Those used less infrequently include azathioprine (AZA),D-pencillamine (D-Pen ),gold
salts,minocycline,and cyclosporine. Many studies have demonstrated the benefit of of DMARD therapy in RA.
The outcome of these trials include control of the symptoms of joint involvement,changes in functional status and quality
of life,and retardation of radiographic evidence of erosions. Costs of the medication and monitoring (including physician
visits and labatory costs),time until expected benefits,and the frequency and potential seriousness of side effects.
The physician should also assess patient factors,such as likelihood of compliance,comorbid diseases,severiy,and prognosis
of the patient's disease, and the physician's own confidence in administeration and monitoring of the drug.
For women of child bearing age,effective contraception is required when most DMARDs are prescribed. The drug regimen
will have to be stopped,or modified if pregnancy,or breast feeding is contemplated.
Based on considerations of safety,convience and cost,many rheumatologist select HCQ or SSZ first,but for the patient
with very active disease or with indicators of a poorer prognosis,MTX or combination therapy would be preferred. If a patient
with RA has not achieved remission or a satisfactory response to the intial trial of DMARD(s), a rheumatologist should be
consulted or employed,if it has not already been done.
MTX as mono-therapy,or as a component of combination therapy should be instituted in patients whose treatment has not
included MTX. For patients in whom MTX is contraindictated,or has failed to achieve satisfactory disease control either because
of lack of efficacy (in doses up to 25 mg/weekly ) or intolerance,treatment with biologic agents,or with other DMARDs,either
alone or in combination is indicated.
HCQ and SSZ: In the last decade,a number of studies have documented the symptomatic benefit of HCQ and SSZ,particularily
for patients with early, milder disease. Although HCQ alone,does not slow radiologic damage,early treatment with HCQ has a
significant impact on long-term patient outcome. Both abdominal cramps and diarrhea are common. HCQ is relatively,well tolerated
and generally,requires no regular laboratory monitoring,although patients need periodic ophthalmology examinations for
early detection of reversible retinal toxicity. The risk of toxicity is increased when the dose exceeds 6mg/kg..
SSZ may act more quickly than HCQ,with benefit sometimes as early as 1 month after beginning therapy,more importantly,SSZ
has been shown to retard x-ray damage. SSZ is usually well tolerated,with most side effects include nausea and abdominal discomfort,occurring
in the the first few months of therapy. The incidence of these side effects is lessened by starting at a low dosage.
Leukopenia is an occasional,more serious side effect that may occur at any time,and periodic laboratory monitoring is
therefore required. Clinical response should be shown in about 4 months,and a need for a change in therapy may be determined
at that time.
Many factors influence the choice of DMARD for the individual patient. Patients and their physicians must select
the initial DMARD (s) based on its relative efficacy,cost,severity of disease,convenience of administration,and requirements
of the monitoring program.
Many rheumatologist select MTX as the initia DMARD,especially for patients whose RA is more active. Because of its favourable
efficacy and toxicity profile,low cost and established track record in the treatment of RA MTX has become the standard by
which new DMARDs are evaluated.
Randomized clinical trials have established the efficacy of MTX in RA, particularily in patients with more severe disease.
Longitudal observational studies and randomized controlled trials show that MTX retards the progression of radiographic erosions.
Observtional studies indicate that more than 50 % of patients who take MTX continue the drug beyond 3 years,which is
longer than any other DMARD. RA patients taking MTX are more likely to discontinue treatment because of adverse reactions
than because of lack of efficacy.
Stomatitis,nausea,diarrhea,and perhaps alopecia caused by MTX may decrease with concomittant folic acid or folinic acid
treatment without significant loss of efficacy. Relative contraindications for MTX therapy are pre existing liver disease,renal
impairement,significant lung disease,or alcohol abuse.
Since the mst frequent adverse reaction in MTX is elavation of liver enzyme levels,their function must be monitored,but
the risk of liver toxicity is very low
Clinical trials have established leflunomide as an alternate to MTX as monotherapy,especially for patients who cannot
tolerate MTX The reduction in RA disease activity and in the rate of radiologic progression achieved by leflunomide
appears to be equivalent to tht of a modest dose of MTX. Leflunomide is also used in combination therapy with MTX,in the absence
of a complete clinical response with full dose MTX.
Five percent of patients recieving leflunomide and up to 60 % of patients recieving MTX plus lefunomide have elevated
liver enzyme levels
Also,refer to Leflunomide or Arava,Enbrel Remicade,Glucosteriods,NSAIDs and DMARDs articles on site,for more information.
Conventional treatment with a single DMARD often fails to adequately control clinical symptoms or to prevent disease
progression As a result rheumatologists are increasingly prescribing combination DMARD therapy. Controversy remains
whether to initiate this type of therapy in a sequential "step-up" approach in patients with persistent active disease in
whom single agents have failed or whether to initiate combination therapy early in the disease course and then apply a "step-down"
approach once adequate disease control is attained. In either case rheumatology referrel is strongly recommended,when considering
this route.
The development of genetically engineered biologic agents that selectively block
cytokines (anticytokine therapy) in the short term,represents a major advance in the treatment of RA. Etanercept is
a recombinant soluable TNF-fc fusion protein,and infliximab is a chimeric (mouse-human ) anti-TNF monoclono antibody.
Infliximab is currently recommended for use only with concomitant MTX therapy. MTX may be used with etanercept or used
alone. Several randomized trials have demonstrated that patients with etanercept alone or with infliximab plus MTX have less
radiographic progression after 1 year rhan patients treated with MTX alone. In the trial with patients made up of early RA
patients,the symptoms and signs of RA improved more rapidly over the first 6 months,with compareable efficacy of the two agents
at 12 months.
The ACR guidlines for monitoring liver toxicity in patients recieving MTX is that a liver biopsy should be performed
in patients who develop abnormal findindings on liver function studies,that persist during treatment or upon discontinuing
the drug. Liver toxicity with MTX is rare.
Although data from randomized trials have not shown an increased frequency of adverse effects,such as infections or malignancies,for
either anti-TNF agent,concerns about the short-term and long-term safety of these agents continue. Enbrel was recently given
a 5 year safety approval in clinical trials.
Clinical trials have demonstrated the efficacy of infliximab and etanercept in improving clinical symptoms and signs
in patients with RA,according to the ACR 20,50,and ACR 70 improvement criteria. Patients with early active RA and those that
had failed previous conventional therapy showed improvements. Anti-TNF agents should be used with caution in patients susceptible
to infection or a history of T.B.,should be avoided in patients with significant chronic infections and should be discontinued,temporarily
in all patients with acute infection
Postmarketing surveillance has yielded reports of septis,tuberculosis.a typical mycobacterial infections,but it not common.
At this time there appears to be no need of routine laboratory testing. Not all patients will respond to TNF therapy. The
main disadavantage is high cost and parental administration.
Minocycline have shown efficacy in certain early,milder type RA patients. Surprisingly it showed efficacy in a subset
of patients who were positive for the HLA shared epitope (HLA-DR4+)(--A.S.) conclusion is further testing should be done on
tetracyclines.
Intramuscular gold treatment is effective,but injections are required every week for 22 weeks before less-frequent
maintaince dose is started. Oralgold althought more convenient has proved less efficacious and is now not commonly used.
Cyclosporine is beneficial and has short-term efficacy to that of D-Pen (not used frequently). the use of cyclosporine,however,has
been limited by its toxicity,expecially hypertension and dose-related renal function 20 %loss of renal function appears to
be reversible for renal function loss,but not entirely. Dose calculation to avoid renal toxicity is more critical with cyclosporine
than with any other DMARD. Cyclosporine plus MTX was found to be more effective than MTX alone but long-term follow up revealed
the development of hypertension and elevated creatinine levels
Low-dose oral glucocorticoids (<10 mg of prednisone daily,or the equivalent) and local injections of glucocortoids
are highly effective for relieving symptoms in patients with active RA. A patient disabled by active polyarthritis may
experience marked and rapid improvement in functional status within a matter of a short period. Frequently,disabling synovitis
recurs when steriods are discontinued,even in patients who are receiving combination therapy. However, many patients are functionally
dependent on steriods and continue them long-term.
Recent evidence suggest that low-dose glucocorticoids slow the rate of joint damage and appear to have disease-modifying
potential Joint damage may increase on discontinuation, Previously it was thought they did nothing to stop disease progression.
The benefits of low-dose glucocorticoids,should always be weighed against their adverse effects which are well documented
elsewhere on site.
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