Rheumatoid Arthritis  - by drdoc on-line


Index

Definition
The Socioeconomic Impact of RA
Aetiology of RA
Articular disease
Diagnostic Criteria
The laboratory
Rheumatoid Factor
Radiology
Extra-articular disease

Therapy in RA
Disease modifying drugs in RA - DMARDS

Biologic drugs
The anti-inflammatory drugs -NSAIDS and COXIBs
Analgesics in RA
Corticosteroids in RA
Chemical Synovectomy in RA
Immunosuppression in RA
Surgery in RA
Paramedical and team approach
Prognosis

 

Definition of Rheumatoid Arthritis (RA):

Rheumatoid Arthritis is a CHRONIC RELAPSING DISEASE characterised by GENERAL ILL HEALTH, CHRONIC SYNOVIAL INFLAMMATION OF JOINT & TENDONS and SYSTEMIC DISEASE

It is common - affecting : 2% of population - with 2.4 million cases estimated in the USA The Annual incidence of new cases is 48 / 100000 of the population .
There is a definite familial tendency and also environmental factors to it’s aetiology It is more common in females : The female : male ratio is 3:1 The mean age at onset is 35-55 years. It has Acute onset in 30% Insidious onset 70% Certain populations are only rarely affected - For example it is rare in rural black patients in South Africa. With urbanisation - the incidence rises.

It has enormous socio-economic impact

There is a :

6 times probability of severe limitation of activity
90% of patients have significantly reduced function after 10 years
50% of patients are severe disability after 10 years
80% of patients are moderately disabled after 17yrs
30-50% of patients are able to work after 15 years
Costs : $777 million (USA 1983) / year
It is a mistake to think that this is a benign disease, and there is significant mortality associated with the disease.
Mortality at 10 years is 26.7% vs 15% for the average population.

Aetiology of RA

The Synovium is the centre of the abnormality in the musculoskeletal manifestations of Rheumatoid Arthritis. This is the lining tissue in the joint, and is similar in structure to the lining around the tendons - the tenosynovium, and the lining surrounding Bursae - which are sacs of fluid containing structures that lubricate tendons as they attach to bone.
The genetic constitution of the synovial tissue is determined by the genetics inherited by the individual, from both parents. The body is able to recognise it’s own tissue as self, and therefore, mounts no immune response to it’s own tissues -a process called immunological tolerance.
However, if for some reason, the body loses its ability to differentiate self from non self, then an immune reaction can be mounted against itself - a process called autoimmune reaction - reaction to “self”.
Thereby there is the activation of the immune system - T Lymphocytes and B Lymphocytes, antibodies, and the whole spectrum of white blood cells and immune chemical modulators - called cytokines, against one’s own body.
An antibody is a protein made by the B cell lymphocyte of the body, under the stimulus of the T lymphocyte cell.
The initial T cell response follows presentation to the T Cell of antigen, by an “antigen presenting cell” - usually a macrophage.
The original stimulating antigen in Rheumatoid Arthritis is not known, but felt by many to be an infective agent - possibly a virus or retroviral particle.
The T Cell requires a particular “self” gene marker to respond to the cell presenting the antigen to it. If it does NOT see these SELF gene markers - no reaction will occur. The “self” gene marker is related to the HLA gene series - that provides markers for risk factor of disease.
They are the CLASS 2 MHC MOLECULES
. The antibodies in Rheumatoid Arthritis include the so called -Rheumatoid Factors are associations with the disease and not necessarily causal.

Thus damage to an organ may expose tissue antigens to the macrophage, and antibodies may therefore be produced as a result of damage, rather than causing the damage in the first place. The whole process therefore is against “self” and hence the terminology - autoimmune - “immune to self”

The SELF genetic markers in the HLA gene structure have been a target of ongoing research. Some of these have been identified as risk factors. They are the genetic constituents that make a patient susceptible to RA. Exposure to the causative antigen or antigens will result in the susceptible host developing RA.

CLASS 2 MHC MOLECULES:

HLA DR1
HLA DR4
The Presence of DR4 enables the prediction of a more severe variety of RA.

THE ANTIGENS either are exposed from our environment - EXOGENOUS antigens, or from within the body itself, possibly exposed to the immune process by an as yet undetermined mechanism. For example - they may be intracellular -inside the cell, and beyond reach of the bodies immune monitoring system. However, if in some way the cell is disrupted, the intracellular contents are exposed to the immune system and a immune reaction follows. These antigens are called ENDOGENOUS antigens.

Some of the EXOGENOUS antigens proposed or implicated in the cause of RA are :

MYCOPLASMA
MYCOBACTERIA
VIRUSES
SPIROCHETES

Some of the ENDOGENOUS antigens proposed are :

COLLAGEN’S
MUCO-POLY-SACCHARIDES
RHEUMATOID FACTORS

Once the T cell is triggered by the macrophage bearing the antigen particles on it’s surface, The T cell sets off a cascade of reactions - involving chemicals called cytokines.
These cytokines then magnify the whole process.

They include :

IL1 -interleuken 1
TNF - Tumor necrosis factor
IL6 - Interleuken 6
CSF - colony stimulating factors

Other Enzymes and chemicals produced also cause damage

Collagenase
Leukotrienes
Prostaglandins
OXYGEN FREE RADICALS

The T cells also stimulate the B cells - which form the antibodies.
The antibodies bind with complement and the antigens to form immune complexes which cause further damage in systemic tissues.

The pathological process is then called an
ARTICULAR PROBLEM - in the joints and
EXTRA-ARTICULAR - in body organs

Articular disease of RA - The joint disease.

If one looks at the synovium microscopically, there is infiltration of Polymorphonuclear cells and macrophages in the tissue, as well as Perivascular lymphocyte infiltration and damage to the lining of blood vessels - the endothelium.
Synovial Inflammation, results in granulation tissue thickening and the spread of this granulation tissue to the cartilage and the margin of the bone and the synovium.
This is called Pannus, and erosion of the Subchondral bone follows with Joint and tendon damage

Clinically the Articular disease starts early on, as an inflammatory disease characterised by:

Pain.
Morning stiffness.
Inflammatory symptoms are more typically felt in the morning.
Midday fatigue
Heat and
Swelling in the joints

It is typically a BILATERAL SYMMETRICAL POLYARTHRITIS

The joints predominately involved are the :
PIP’s
MCP
WRISTS
MTP’s
ANKLES
KNEES
NECK
SHOULDERS
ELBOWS
HIPS

Early hand swelling Early wrist and finger swelling
Early swelling of the wrist Early swelling of the knees
Advanced disease with ulnar deviation Erosions of the wrist

However , with time the disease becomes chronic, and there is erosion and damage to the underlying cartilage and bone of the joints. The bone becomes thinner - osteopenic, and the cartilage becomes narrowed and erodes.
The damage is NOT reversible once the cartilage has been lost, and progression with mechanical change, becomes inevitable.
Over years, The inflammation will then start to subside, and the symptoms change - to pain later in the day, and less morning stiffness.
The joints are deformed and function deteriorates due to this deformity.

Diagnostic criteria have been drawn up by the ACR
One requires 4 out of the 11 for the diagnosis.

The diagnostic criteria for Rheumatoid arthritis

MORNING STIFFNESS greater than 1 HOUR
SOFT TISSUE SWELLING IN A HAND JOINT
SOFT TISSUE SWELLING in 3 out of 14 joint GROUPS
PIP'S, MCP'S, WRISTS, ELBOWS, KNEES, ANKLES, MTP’s
SYMMETRICAL SWELLING IN ONE JOINT AREA
RHEUMATOID NODULE
RHEUMATOID FACTOR
RADIOGRAPHIC CHANGES IN THE WRIST OR HANDS. (POROSIS / EROSION)

This does NOT have to mean that therapy should not be commenced until all criteria are present, as they can develop over time. A strong suspicion for the diagnosis is sufficient with a diagnosis of probable RA.

The assessment of the RA patient

A. The History

1. Evaluation of the history including onset and duration as well as distribution of joint disease and social and functional impact on the patient and the family.

2. Assessment of pain, stiffness and function
Pain visual analogue scores can be used to assess pain - to try and obtain some objectivity in the recording process.
Many health assessment questionnaires are available and reproducible, but a simple functional assessment can be graded:

Stage 1. Independent
Stage 2. Some discomfort but can perform all activity
Stage 3. Impaired but can be responsible for self care
Stage 4. Dependent on others

B. A full comprehensive General, System, and Musculoskeletal examination

This includes an examination of ALL the joints in the body, and regional tendon and bursal sites.

Joint counts and scores as well as the Ritchie index can be calculated.
The latter is a score of tenderness performed on many joints, as a response to pressure.

A score of :

0. Painless.
1. Tender.
2. Wince / Grimace.
4. Withdrawal of the limb.

An assessment of deformity in each joint should also be made.

Blood Tests and the Laboratory

This assists not only in diagnosis, but also in quantifying active disease.
The blood tests are an adjunct to the clinical assessment. They do not replace it.
The lab tests must ALWAYS be interpreted in the clinical context, and NOT in isolation.
I generally ask for :
FBC - full blood count.
ESR - sedimentation rate - this is useful as a screen for inflammation in the body, but is non specific and not infallible.
CRP - C-Reactive protein. This is increasingly being used as a marker of inflammation, and activity of the disease.
It is produced in the liver as a response to inflammation.
RHEUMATOID FACTOR

The rheumatoid factors are ANTIBODIES TO a part (Fc PORTION) of HUMAN Immunoglobulin (IgG) .
They are detected by AGGLUTINATION TESTS.

There are 2 main types :
SCAT : the Sheep cell agglutination test - MORE SPECIFIC
LATEX : Where latex particles are used in the detection process - MORE SENSITIVE

Of note is that 1-5% of NORMAL people in the population are positive (NB this increases with AGE ) Only 75-85 % of RA patients are positive.
Therefore they are not absolutely necessary for the diagnosis.
But a high Rheumatoid factor is a marker of more severe disease.

Positive Rheumatoid Factor is sometimes seen :

1. In several Rheumatic and autoimmune diseases including:

RA
SJOGREN
SLE/SCLERODERMA
POLYMYOSITIS
Coeliac disease
Chronic Active hepatitis
INTERSTITIAL PULMONARY FIBROSIS
WALDENSTROM’S macroglobulinaemia

2. As well as several general medical disorders - including :

ENDOCARDITIS
TB
SYPHILIS
LEPROSY
SCHISTOSOMIASIS - BILHARZIA

Radiology - X-Rays

I generally ask for X-Rays of the hands and feet.
If clinically indicated I ask for a Chest Xray and if there are cervical spine symptoms - I ask for a cervical XRAY - including flexion and extension views.
Erosions in general form within the first 2 years.

The changes on Xray go through several stages.
1. Soft tissue thickening
2. Periarticular porosis - regional osteopenia.
3. Joint space narrowing
4. Subchondral cyst and cortical margin erosions
5. Progressive erosive disease with joint destruction.

In the neck it is important to look for instability that identifies danger to the spinal cord - especially, atlanto-axial and subaxial subluxation, and basilar settling.

A chest Xray should also be done where appropriate - either for lung disease or to check the lung status with drugs - especially methotrexate and Sulphasalazine.

Rheumatoid Arthritis - Extra-articular involvement.

It is vital to understand that RA is NOT just a joint disease and that many organs can be involved.

These include :

Haematological problems :

Anaemia - either from the disease as an anaemia of chronic disease, or from Iron deficiency as a complication of blood loss with the antiinflammatory drugs, or as a complication of the disease modifying drugs -such as gold / Penicillamine / methotrexate.
Neutropenia - seen with splenomegaly in “Felty syndrome” in RA, - which is almost always seen in DR4 positive patients, and as a complication of DMARD therapy - especially Gold, Penicillamine, and Methotrexate.

Go to Additional information on anaemia in RA

Pulmonary problems :

These include
PLEURITIS / PLEURAL EFFUSION - inflammation of the lining of the lung.
PNEUMONITIS - inflammation within the lung tissue - similar to pneumonia.
PULMONARY Nodules - pulmonary bleeding.
INTERSTITIAL LUNG DISEASE - a progressive scarring of the lung tissue. This can be extensive and can occur with nodules in Caplan’s syndrome - described first in Welsh Coal miners with Rheumatoid arthritis
Bronchiectasis - chronic suppurative infection around the bronchi and bronchioles has also been described associated with RA.

Cardiac Involvement-

The commonest involvement is :
PERICARDITIS - inflammation of the lining around the heart is seen in up to 40% and presents with chest pain , malaise and sometimes breathlessness. The clinical findings may be absent with a pericardial effusion identified on an XRAY or cardiac ultrasound.. ie it can be ASSYMPTOMATIC. However a pericardial RUB may be heard on auscultation of the heart on examination. Occasionally the fluid in the pericardial space can increase in volume, and rarely the fluid in the confined space can compress the heart itself and result in CARDIAC TAMPONADE- with heart failure. In addition, scarring down of the pericardium can result in CARDIAC CONSTRICTION, another cause of right heart failure.
MYOCARDIAL nodules can be found on the heart valves and in the conduction tissue - with complications of Arrhythmia.
Rarely the actual muscle itself can be inflamed with a MYOCARDITIS.

Neurological problems

The commonest neurological abnormalities are secondary to compression to neural tissue. This can occur peripherally in the wrist as c
arpal tunnel syndrome., or other neuropathies - ie at the elbow affecting the ulnar nerve.
Compression of the spinal cord is a well documented complication of cervical spine disease. The latter is proportional to peripheral erosive, disease, and the Doctor should remain alert to this potential. More specific disease can be seen as a consequence of
vasculitis - either as mononeuritis multiplex
- with an ischaemic damage to the nerves - causing localized sensory or motor paralysis in peripheral limbs.

Vasculopathy

This is most frequently identified with mononeuritis multiplex and with intractable skin ulcers - usually on the outer aspect of the ankles and feet.
Small vessel changes with nail-fold infarcts are a cause for concern and monitoring.
Involvement of nerves and large skin ulcers usually demand aggressive therapy with immunosuppression and cortisone.
The investigation of this may include a sural nerve biopsy, rectal or abdominal fat biopsy, or even angiography.
A nerve conduction study by a neurologist will usually identify mononeuritis- regarded as a potential rheumatological emergency.
Medium vessels can also be involved and a disease spectrum similar to Polyarteritis Nodosa can result..

Skin Involvement :

Subcutaneous Nodules are seen especially the extensor aspect of the elbows and forearms, and occipital region, but can be found virtually anywhere. They are seen in 25% of patients, and also potentially reflect a more severe disease, and seropositivity for rheumatoid factor.
Fragile skin is frequent, as is bruising of the skin. These are aggravated by use of Corticosteroids in a dose related manner.
The presence of skin ulcers and nail fold infarcts an splinter haemorrhage are major cause for concern as they reflect a possible vasculitis.

Go to additional information on the Skin in RA

Ocular involvement :

Ocular involvement is a frequent finding- and the anatomical site of inflammation determines the requirement for therapy.
Scleritis, Iritis or iridocyclitis -indicates an involvement of the iris, and uvea, and cause red, usually painful eyes, possibly with blurred vision. Raised yellow scleral nodules may be seen with the scleritis. Occasionally, the sclera thins - and appears bluish as the pigmented choroid is seen through the thinned membrane - this is called scleromalacia. Perforation may occur - scleromalacia perforans.
Superficial layer involvement is called Episcleritis, and is usually red, and mildly painful.

The differentiation between scleritis , which is serious versus Episcleritis may be assisted with the use of slit lamp microscopy - by an ophthalmologist.

However a bedside technique is possible to differentiate them, pending ophthalmology assessment. If you press on the sclera of a patient with an Episcleritis, the redness and vessels on the surface blanche and go pale- with blood and redness returning on relieving the pressure.

With a scleritis, the redness is deeper and does not blanche with pressure. Therapy for scleritis requires steroid drops and sometimes systemic immunosuppression.

Sjogren syndrome - dry eyes is an additional cause of eye disease - with a lack of tear film, and lubrication. This results in recurrent conjunctivitis as well as corneal ulceration.
Treatment is with artificial tears, applied frequently.

Renal disease.

The main problems seen with the kidney are more related to therapy, rather than the arthritis. Antiinflammatories and analgesics can cause several types of nephritis- especially interstitial nephritis.
Renal toxicity can be seen especially with Gold, Penicillamine, cyclosporine, and occasionally Sulphasalazine and methotrexate.
Monitoring of the urine for blood and protein is necessary as a routine for patients on these medications.

The Therapy of Rheumatoid arthritis

In general treatment is individually determined.
Before therapy several questions need answers before therapy can be chosen.

1. How long has the disease been present.
2. What is the current activity of the disease.
3. How much damage is present already.
4. What is the general medical condition of the patient.
5. What coincidental illnesses are present - ie diabetes / peptic ulcer / heart disease.
6. What is the age of the patient.
7. How accessible is the patients location for monitoring of the potential side effects of medications that can be used.

General approach -

Unless the disease has been present for a long time and is not currently active, It is not adequate to treat these patients with antiinflammatories alone. We know that most patients will develop their erosions and damage in the first 2 years. We also know that the immune system becomes entrenched early on in disease. Therefore early and aggressive intervention is required.
These group of drugs are the
DMARDS - or disease modifying anti rheumatic drugs. They include:

Methotrexate.(ledertrexate)
ARAVA - Leflunomide 
Salazopyrine (Sulphasalazine Azulphidine)
Gold - injectable (Myocrisin) or oral (ridaura)
Antimalarials (Plaquenil, Nivaquine etc.)
Penicillamine
Cyclosporine
Azathioprine

In general, we do not use gold or penicillamine anymore, as they are essentially obsolete. Azathioprine, also has largely become obsolete and has been replaced by the biologics.

Combinations of the DMARD drugs are being used more and more frequently.
(Go to combination therapy webpage)

In general they take 2 to 3 months to START working.
The aim of therapy is to establish remission.
The concept of remission is CONTROL not CURE.
The medications have to be continued ongoing - stopping usually results in flares within 1-2 months. Patients who go out of remission on stopping the drugs - frequently find that to re-establish remission is much harder the second time.

However if there is a failure of response to the first line response of disease modifying therapy, then the patient should be considered for the use of new biologic therapy.  These drugs are costly, and do have  potential side-effects, and therefore it is our policy to use them as a second line approach, rather than first line.

Biologic therapy

Biologic therapy has been the major development in the field of Rheumatology over the last 10 years. Several different drugs are now available.  To understand the mechanism of these drugs, an understanding of the immune system is ideally required.(Click here to go to immune system review). 

Monitoring of biologic therapy is required to assess response. Accordingly, we do joint counts and use questionnaires such as the health assessment questionnaire, and patient and physician global scoring. We measure, the C-reactive protein and sedimentation rate as an objective measure of inflammation. Various scores have been designed including the disease activity score --DAS, and disease activity index -SDAI. We follow these responses serially over time. This process is critical as an objective measure of response to the drugs.

Response scores have had been used in trials include the American College of rheumatology -- ACR, 20, 50, 70 percent responses. These imply that at least, that percentage of patients respectively will respond to the drug.

The responses of biologic drugs in trials have been largely consistent across all classes of drug. No major competitive trials have been done comparing individual agents, that shows superiority of one versus another. Almost all trials show approximately 70% ACR 20 response, 50% ACR 50 response and 20% ACR 70 response. What does differentiate the drugs however is side effect, administration mechanism, frequency of application and therefore choice of drug depends on individual factors. In addition, there are cost differences. However, all the drugs have considerable cost.

Reduction in radiological damage is now well documented in several trials of these drugs with a reduction in erosions and the effect on bone. This has been one of the most interesting benefits of the use of biologic drugs.

Drugs available:

Drug Mechanism Administration
Infliximab, Remicade, Revellex Anti TNF chimeric antibody Intravenous infusion
Etanercept, Enbrel Recombinant soluble TNF receptor fusion protein Subcutaneous injection.
Adalimumab, Humira  anti-TNF  Subcutaneous Injection
Anakinra, Kineret  Interleukin-1 receptor antagonist  Subcutaneous injection
Abatacept, Orencia Co-stimulant antagonist CTLAV4-Ig fusion protein Intravenous infusion
Tocilizumab, RoActemra, Actemra Interleukin 6 receptor antagonist  Intravenous infusion 
Rituximab, Mabthera Anti CD20- B-cell antagonist Intravenous Infusions

Agents that oppose the action of tumour necrosis factor

The introduction of Tumor necrosis factor / monoclonal antibody therapy has been extremely exciting. tumour necrosis factor is one of the key mechanisms of inflammation (Click here to go to immune system review). Mechanisms to antagonize the effect of tumour necrosis factor, include either a direct binding of a synthetic molecule or antibody to Tumour necrosis factor.  Or secondly, prevention of tumour necrosis factor reaching the receptor of the cell by utilizing circulating receptor. The drugs in this class of drugs have a potential to cause potent immunosuppression.  This provides long-term issues such as susceptibility to infection.  These infections include the potential for unusual infections such as tuberculosis or fungal infections.  In Africa we have high levels of tuberculosis in our community.  Here and even worldwide, we screen for tuberculosis before considering using this form of treatment.  This includes x-ray of the chest and skin testing.  If skin testing is positive, we initiate treatment for latent tuberculosis, ideally, for one to two months before starting treatment.  This includes isoniazid -- INH and possibly rifampicin therapy.  This treatment would then be continued for up to six months concurrent with the anti-tumor necrosis factor therapy. Other infections, that may be aggravated by the drugs include upper respiratory infections, sinus infections, fungal infections, and histoplasmosis and pneumocystis lung infections.

Other side effects, and to this group include the potential for malignancy, such as lymphoma.  This is controversial, as multiple studies suggest that the underlying autoimmune diseases such as rheumatoid arthritis, also potentially cause lymphoma.  Concurrent use of these drugs with pre-existing malignancy is controversial, and has to be considered depending on the individual patient. 

Infliximab -- Remicade -- REVELLEX

Infliximab is a antibody to the tumour necrosis factor itself.  However, it consists of mainly human construction, but there is a small mouse component to the antibody.  This aggravates allergy problems.  The drug is given as a fusion at baseline, two weeks, four weeks, eight weeks and then every eight weeks thereafter.  Infusion centres are required as the is a potential for allergy during the infusion, which can be either mild such as rashes or severe.  This includes a potential for anaphylaxis, including bronchospasm wheezing or circulatory collapse.  Therefore I personally premedicate the patient with hydrocortisone 100 mg and phenergan 25mg intravenous antihistamine.  This prevents an infusion reaction.  The use of Phenergan does cause some drowsiness, and therefore I  instruct the patient not to drive home afterwards. Successive infusions, frequently are associated with reduced risk, but a healthy respect for the drug is required by the practitioner.infliximab

The dose is 3 mg per kilogram for rheumatoid arthritis and 5 mg per kilogram for spondyloarthropathy or inflammatory bowel disease.

The drug is given with a biological filter. It is given as a slow infusion. Supervision of the patient is required at all times. The results of the treatment excellent and noticed rapidly by the patient. Some people even notice some benefit within hours.

However over time, the effect of the drug sometimes reduces and more frequent infusions or higher doses may be required.

An additional problem is the development of antibodies to the drug. Therefore, to prevent this co-use of methotrexate with infliximab is recommended. The methotrexate is used in the standard weekly oral method. Blood tests are therefore required to monitor the methotrexate, as per usual. Trials show superiority of methotrexate with infliximab compared to infliximab alone.

Further, if patients stop infliximab for whatever reason, the effect of antibodies on the drug builds up and reintroduction of the drug after several months fails frequently to produce any response.

Etanercept -- Enbrel

An alternative to direct anti- tumour necrosis factor antibody, a natural mechanism exists; of soluble Tumor necrosis factor receptors circulating in solution to oppose circulating tumour necrosis factor. Synthetic production of this circulating tumour necrosis factor receptor has been successfully processed by joining two molecules together as a fusion protein.

Enbrel consists of 2, P-75 TNF receptor proteins and human immunoglobulin, joined at the Fc portion. The process of joining two receptor molecules effectively increases the half life of the molecule. Natural circulating TNF receptor has an extremely short half life and cannot be used therapeutically.

Enbrel is given as an injection subcutaneously, twice a week. The drug is provided as a powder and fluid that requires to be mixed by the patient before injection. Co-use with methotrexate, has also been shown to be beneficial.

Side-effects of the drug concluded standard anti-TNF concerns, such as risk of infections. Injection site reactions and allergies are common and are usually minor. Sinus and upper respiratory tract infections are relatively common, but usually mild. Severe infections require cessation of drug. Other extremely rare side effects include a demyelination syndrome similar to multiple sclerosis.

On the whole, the drug is easy to use and patient friendly. Response rates are excellent and similar to other anti-tumor necrosis factor drugs. The drug has been used in rheumatoid arthritis and spondyloarthropathy including ankylosing spondylitis and psoriasis. It has been used with wide experience in juvenile arthritis.

Adalimumab --Humira 

Humira is a humanised antibody to Tumor necrosis factor, and has no mouse or foreign component, and therefore has less allergy. It is given as an injection of 40 mg subcutaneous every two weeks. The pre-filled syringe requires no reconstitution by the patient and is very easy to give by the patient. The injection has some problems with local allergy and has been described as slightly painful by some patients. Results however are excellent, rapid and similar to other anti-TNF drugs. Side-effects are also similar with chronic infection such as tuberculosis recurrence the major concern, as with other anti-TNF drugs. co-use with methotrexate is not thought to be as important as compared to etanercept or infliximab. The drug has been used in both rheumatoid arthritis as well as the spondyloarthropathy and juvenile forms of arthritis.

Rituximab -- Mabthera.

This is a B-cell targeting therapy. It is a genetically engineered anti CD 20 monoclonal antibody that selectively targets CD 20 positive B-cells. CD 20 positive B-cells do not include the stem cells or the mature of plasma cells which make the antibodies. Therefore existing immune response persists. Binding to the B-cell triggers damage and apoptosis or death of CD 20 positive B-cells.

The drug has largely been used after a failure of tumour necrosis factor drugs, and therefore is thought to be a second line of biologic therapy. Recent evidence however suggests that the failure of response still allows reintroduction of anti-TNF therapy.mabthera

Trials of Rituximab have been done in patients with rheumatoid arthritis in particular. The drug is given as an infusion of 1000 mg on day 1 and a day 15, and is usually followed with a second series of infusions after six months.

The drug has a allergic potential, including that of anaphylaxis, and requires supervision and monitoring in an infusion centre or high care facility. Because of the risk of allergy, I premedicate my patients with hydrocortisone 100 milligrams and Phenergan -- antihistamine 25 mg before the infusion. This prevents incidence of allergy. Subsequent infusions produce reduced risk of allergy.

Side effects include infection risks. However, the risk of chronic infection such as tuberculosis does not exist with this group of therapy, which gives it a major advantage in areas of high tuberculosis prevalence.

Studies showed that the B-cell levels drop within three weeks. Response to treatment is similar overall to the anti-TNF drugs, with 70% ACR 20, 50% ACR 50 and 20% ACR 70 responses. Radiographic progression is inhibited. The response to the drug may last several months before repeat infusion is required.

Abatacept -- Orencia

abataceptThis drug has a different mechanism to other biologic drugs. This opposes co-stimulatory molecules which assist with binding of immune cells to T-cells. CDs, 28 is one of the surface markers on a T-cell, that assist with binding of CD 80/CD 86 surface markers of antigen presentation cells to the T-cell. This facilitates the immune response. Abatacept consists of immunoglobulins bound to CTLA4, which binds to CD80/CD86, and prevents or suppresses T-cell activation. The drug is given as a 30 minute infusion at baseline, two weeks, and thereafter every four weeks. Responses are similar to other biologics. It is largely used for patients with inadequate response to anti-tumor necrosis factor therapy -- as a second line approach. Side effects include infections such as respiratory or urine tract infections, and also tuberculosis is a potential problem similar to other anti-tumor necrosis factor drugs. The side effects are therefore similar to all other biologic drugs.

Tocilizumab -- RoActemra

Tocilizumab is one of the newest biologic drugs, and one of the most exciting. It consists of an anti-IL-6 mechanism. Tocilizumab is an anti-IL-6 monoclonal antibody. IL-6 is closely involved in the cytokine or immune mechanism network in inflammatory arthritis. It is also associated with the mechanisms of osteoporosis, and erosion formation by the stimulation of RANK Ligand. (Receptor activator of NF Kappa beta), which stimulates the osteoclast activity in bone. It also stimulates the liver to produce acute phase proteins such as C. reactive protein, CRP.

Therefore, IL6 antagonism is theoretically a direct opposer of the immune mechanism of rheumatic disease, and associated bone damage. Trials show and confirm a reduction in joint inflammation activity, with good response to rheumatoid arthritis inflammation. There is a 70% ACR 20, 40% ACR 50 and 20% ACR 70 response in trials.

The dose is 4 mg per kilogram to 8 mg per kilogram of Tocilizumab. It is given as an infusion every four weeks. Reduction in CRP levels is noted. Improvement in hemoglobin is observed and a reduction in bony erosions and joint damage confirmed.However, as expected, the same side effects are observed as with other biologic drugs, with infections being the major concern. Elevation in lipid and cholesterol parameters are observed. A reduction in white cell and platelet counts has also been observed. Caution is therefore required in patients with low white cell count and low platelet count. Mild increases in liver enzymes have been observed and liver function test monitoring for the first six months is advised on two monthly basis.

Remission data suggest that long-term remission is possible.

Because this drug is used in patients who have failed anti-tumor necrosis factor therapy, studies have shown that responses to Tocilizumab reduced the greater the number of TNF drugs that had been used and failed in the past.

Co-treatment with methotrexate is not required, but preferable. If used with methotrexate, standard monitoring of methotrexate is required over time.. 

Biologic Summary

 

Etanercept

Enbrel

Infliximab

Remicade

Revellex

Adalimumab

Humira

Anakinra

Kineret

Abatacept

Orencia

Rituximab

Rituxan

Mabthera

Tocilizumab

Roactemra

Target

TNF

TNF

TNF

IL-1 Receptor

T-Cell Activation

B-Cell

IL-6

Half Life

3-5  Days

8-10 Days

10-20 Days

4-6 Hrs

13-16 Days

19 Days

10 days

Construct

Human

Chimeric

Human

Human

Human

Chimeric

Human

Dosing

Once Biweekly-weekly

Once every 4-8 weeks

Once every 1-2 weeks

Once Daily

Once Monthly

Twice every 6-12 months

Monthly

Route

Sub-Cut

I.V.

Sub-Cut

Sub-Cut

I.V.

I.V.

I.V.

CRITERIA FOR REMISSION IN RA

STIFFNESS < 15 MINS
NO FATIGUE
NO C/O JOINT PAIN
NO JOINT TENDERNESS
NO SOFT TISSUE SWELLING
ESR < 30 (Females) <20 (Males)

The older studies showed no improvement in erosions with DMARDS, because the policy in the past, was to start late in the disease - where it was thought that the risk benefit ratios warranted the drug. However we now know that most erosions occur in the first 2 years of disease, and the immune system abnormality becomes entrenched with poor response to immune modulators. Therefore when you read of trials in RA - look at the duration of disease in the patients studied.
Even today - there are still studies coming out by the dozen - with mean duration of disease 5-15 years at start of therapy. These studies, I and many other Rheumatologists feel - are re-inventing the wheel.

That work HAS been done before, and is of questionable validity when extrapolated to early RA patients.

Those newer studies coming out looking at disease early on are showing reduction in erosion scores - especially with methotrexate ,cyclosporine, Sulphasalazine, and this has been shown more recently with low dose prednisone as well.
What still is seen -for early AND LATE disease is an improvement in FUNCTION and swollen joint scores, and quality of life. The erosion and X-RAY appearance does NOT necessarily correlate with function. An RA patient is interested in his/her FUNCTION...that’s the bottom line and THAT’S where the DMARDS come out on top.

Antiinflammatories (NSAIDS) do NOT show any long term benefit to the arthritis as they only change the bodies response to the process - ie the EFFECT rather than the cause. They are PURELY symptomatic therapy. The body deteriorates and overall function deteriorates without the patient realising it - until the disability is there. However whilst waiting for the remission therapy to start working, it is important to get symptomatic control. The symptom control is achieved through the use of the Antiinflammatories and Analgesics. The Antiinflammatories are a group of compounds that interfere with the COX - cyclooxygenase enzyme.
These are now categorised as the COX 1 and COX 2 enzyme systems
, and are discussed elsewhere on the website.
The antiinflammatories
DO NOT CHANGE THE COURSE OF THE DISEASE.
There are numerous antiinflammatories on the market.
These have now been "almost made redundant" with the release of COXIB drugs such as Celecoxib (Celebrex) and Rofecoxib (Vioxx). These latter drugs are as effective as the older NSAIDS, but are MUCH safer in terms of gastric side effects, as they do not inhibit COX1. However there are those patients who may not respond or for other reasons may not tolerate the new generation products, and these people may require the older NSAIDS.


NSAIDS
can be classified according to their structure.

1. Carboxylic Acids

PHENYLACETIC ACIDS
DICLOPHENAC
FENCLOFENAC
CARBO HETEROCYCLIC ACIDS
INDOMETHACIN
SULINDAC
TOLMETIN
SALICYLIC ACIDS
ASPIRIN
PROPRIONIC ACIDS
IBU/KETO/FENO/FLURBI PROFEN
NAPROXEN
ANTHRANILIC ACIDS
MECLOFENAMIC ACID
FLUFENAMIC ACID

2. PYRAZOLONES BUTAZONES PROPAZONES

OXICAMS
PIROXICAM
MELOXICAM

3. THE COXIBS

CELECOXIB
Valdecoxib
Etoricoxib
Lumiracoxib - not yet available
(Rofecoxib - now withdrawn from the market)

The main problem with the antiinflammatory drugs is gastric toxicity - with development of peptic - especially, gastric erosions, and ulceration.
This is NOT equal to all of the products - and depends on the COX 1: COX 2 ratios.
The smaller the ratio - the higher the selectivity. and the lower the side effects theoretically.
The rank order tends to vary slightly between different studies.
There is little difference between the ratios of ibuprofen and diclofenac, but statistically significant difference with piroxicam which is poorly selective, and Meloxicam which has a higher selectivity.

Diclofenac meloxicam and ibuprofen are perhaps one of the better of the current agents on selectivity profile.
Meloxicam is only slightly more selective AND IS NOT A COX2 SPECIFIC DRUG. 
The new generation products - the COXIBS are very exciting and change the whole therapy of the disease.
Readers are recommended to refer to the
COX 2 articles on this website for details.
IF people cannot tolerate the COXIBs, such as Celecoxib, or Valdecoxib,
My preference to avoid gastropathy problems in the NSAIDS, is the combination of the NSAID, where possible, with a gastric mucosal barrier protector - prostaglandin E2 agonist called misoprostol (Cytotec). These are discussed elsewhere on the web-site. In fact I commonly use a combination of misoprostol and diclofenac tablet, available in South Africa, and other countries (as Arthrotec), but not yet in the United States of America. There are certain contraindications to misoprostol - especially pregnancy, and it should not be used in the absence of contraception, if used in patients of childbearing age groups. The use of cytoprotection reduces ulcer related problems by over 50%. It therefore becomes even more appropriate when used in high risk patients - ie previous ulcer, or the elderly.

Other toxicity problems with the NSAIDs include renal toxicity and hypersensitivity. Caution especially needs to be used in the elderly, and in dehydration states. Interaction with warfarin / Coumadin is also a potential problem

The analgesics - including paracetomol, and paracetomol - codeine combination compounds are particularly useful for the symptom of pain, with or without the antiinflammatories.

In general, the greater the stiffness, the greater the place of the NSAIDs, whilst the lower the stiffness is as a complaint, the greater the use of analgesics. Occasionally, there is a place for stronger analgesia - including propoxyphene, or tramadol.

Corticosteroids : The use of Corticosteroids in the past was seen as a major advance in the therapy for Rheumatoid arthritis.
High doses were employed.
However the considerable side effect profile - resulted in a complete reversal of the use of these for Articular RA. Over the last 5 years, there has been a major movement back to these agents. However, the doses used have been reduced considerably, and the safety profile is now seen as good, as long as the doses are kept below 7.5 - 10mg.
Exceptions to this low dose principle are the presence of life threatening systemic disease - especially cardiac, respiratory and vasculitis involvement.

For Articular RA, my usual regimen is to start at 7.5mg per day and maintain this dose until the DMARDS take effect. This is usually at approximately 2 months. I then start a slow reduction - to 5mg per day for a further month to 2 months, and then 2.5mg per day. Further reduction then depends on progress. If possible, the dose is then reduced to 2.5mg alternate day, an subsequently to 2.5mg every third day.
Only then do I consider stopping the drug.
If at any step reduction, the patient becomes stiff or swollen, I maintain the previous level a further month before attempting a reduction again.
If a small maintenance dose is still required - it is almost invariably at 2.5 mg per day or less.

The use of intraarticular injections of steroid are invaluable in the management of RA. The decision to inject is made especially if the joint, tendon, or bursa concerned is out of phase with the rest of the joints.

The choice of steroid I use is..
Triamcinolone hexacetonide for deep bursae and joints.
Betamethasone disodium phosphate and acetate for more superficial structures.

Occasionally one sees atrophy of the skin or subcutaneous fat if the injection is superficial, therefore placement and choice of agent is important. There are few other significant side effects.
Occasionally one sees a reaction to the crystal content of the steroid, and this manifests as an acute joint flare that settles after 24 hours.

I generally allow 3 injections maximally in weight bearing joints. I allow 4 per year in a non-weight bearing joint or soft tissue structure. I combine the injection with 2% remicaine solution as a local anaesthetic in the same bolus. The injection should NOT be painful, but can be mildly uncomfortable some hours later, before subsiding again and helping the problem in 24-48 hours.

I always tell my patients that they should have relative rest for 48 hours following a weight bearing joint injection

Chemical Synovectomy

Mustine or Yttrium intra-articular injections may be used for joints which are resistant to therapy, with ongoing swelling - and effectively constitute a chemical synovectomy.

Immunosupression - This includes cytotoxic therapy and is reviewed elsewhere on the website. It is reserved especially for organ specific and life threatening disease.

It includes predominately the use of Azathioprine, Cyclophosphamide and Chlorambucil
Cyclosporine is increasingly being used for management of severe RA, often together with methotrexate, with excellent results.
However, it is very costly, and care must be exercised regarding renal function and hypertension.

Surgery in RA

Surgery has advanced tremendously in offering patients with disability and functional impairment, a new opportunity to mobilise again.

Replacement Arthroplasty has been especially successful in the hip and knee. Shoulder Arthroplasty is also successful, as is the elbow. The wrist Arthroplasty is not yet as successful, and surgery there is often done as a fusion in a functional position (arthrodesis) For the finger MCP and PIP joints, Replacement Arthroplasty is the surgery of choice for the joint mechanical problems, where function is disturbed.
Tendon repair and relocation, is used for tendon rupture and the tendon related deformity in the hands.

Preventative surgery is used for prominence of the ulnar head at the wrist - to prevent extensor tendon rupture of the 5th, 4th and 3rd fingers in the hands.
It is also beneficial as synovectomy of the joints - in particular at the knee via arthroscopy and at the wrist and elbow.

Ankle and subtalar surgery is again extremely difficult, and replacement Arthroplasty has not yet been refined for these joints. Arthrodesis - fusion in a proper position remains the main surgical intervention here.

For the feet, MTP joints, - Replacement Arthroplasty is the surgery of choice for mechanical problems, although Excision Arthroplasty is also common together with Osteotomy procedures.

Paramedical Therapy

These provide a holistic team approach, and centre on
Physical therapists,
Nurses,
Educators,
Occupational therapists,
Orthotists
Dieticians,
Social workers, and the
families and
patients themselves.

The Physical Therapist plays a major role in assessing function and activity and implementing a program to help pain relief initially and a rehabilitation program in the long term.

Acute management of the physical therapist:
Rest
Immobilization
Maintain Joint Range of movement by Active Movement and Passive Stretch exercises to maintain / Restore Muscle Power
Skin traction
Heat / Laser / Ultrasound - especially to the soft tissues
Hydrotherapy

As the joint becomes less swollen - movement is encouraged and more active exercises resume against progressive Resistance.

Hydrotherapy and floor exercises are extremely useful to restore muscle tone and power.

Wasting of muscles around an inflamed joint is a rapid process, and restoration of the muscles are much more difficult to achieve.

Occupational Therapists - these professionals look at the function of the patient in the context of their disability and teach and provide:
Joint protection
Assistant devices
Splints
Resting Splints - during acute phase and
Serial Splints, progressing to
Semistatic resting and
Dynamic splints.

The use of assistant devices and education on the activities of daily living is invaluable - as we take so much for granted that arthritis patients must face every day of their lives.

The Dietician.

Diet is not, as frequently claimed, the answer.
Certain foods irritate certain patients as individuals.
Moderation is the key.
Diet is only a marginal factor
Vegetarians are NOT immune from developing any type of arthritis.
Red meat I however tend to discourage.
If an individual finds a particular food irritant to the joints I suggest they LEAVE that foodstuff OUT. But people are different and what is good for one is not necessarily good for others, and Vice Versa.
I encourage a balanced diet.
I encourage calcium supplement, especially in patients on steroids, possibly with vitamin D as well.
I encourage weight reduction where necessary.

Similarly malnourishment may occur and supplementation is given for general health reasons and not as a cure for the Arthritis itself

The Orthotist assists in provision of footwear adjustment and shoe inserts to assist in providing proper foot-care. They also provide splints as required especially for the lower limb.

Rheumatoid Arthritis : The prognosis
Poorer predictors of outcome are seen with :

MALES
ONSET BEFORE AGE 50
DISEASE > 5 YRS BEFORE THERAPY
>20 AFFECTED JOINTS
LACK OF FORMAL EDUCATION
LOW SOCIO-ECONOMIC STATUS
POOR FUNCTIONAL CLASS at onset of disease
RHEUMATOID FACTOR - high levels
EXTRA ARTICULAR INVOLVEMENT

There is a Reduced life expectancy
26.7% Mortality at 10 years (vs 15% average population)

Cause of death in patients arises from :

CARDIOVASCULAR causes/ disease 40%
MALIGNANCY 14%
INFECTION 9%
RENAL DISEASE 8%
RESPIRATORY DISEASE 7%
EXTRA-ARTICULAR DISEASE 5%
GIT DISEASE 4%
THERAPY ITSELF

The latter strongly emphasises the point that an aggressive approach may be necessary, but in addition one should point out, that if potentially toxic medications are used, the Practitioner should have experience in their side effect profile, and if not, a Rheumatologist, where available, should be the Specialist of choice in looking after patients with Rheumatoid arthritis.

My recommendation is that ALL patients with RA should see a Rheumatologist.
Ultimately, I want my patients to be educated and responsible for their own care as part of the team.
They must know the disease.
They must know what I am doing and why.
They must ask questions.
There is NO SUCH THING AS A STUPID QUESTION.
They must be responsible for clinic attendance, and blood monitoring of potential side effects.
EDUCATION I FIND MAKES ALL THE DIFFERENCE.
An educated patient also keeps me on my toes, and up to date, reading, researching, and striving for the answer we all await - THE CURE.

 

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Go to NSAIDS page

Go to disease modifying therapy in RA - DMARDs in RA
Go to a review of therapy for RA and OA (osteoarthritis) for the GP / family physician
Go to immunosupression / cytotoxics in the rheumatic disease page
Go to combination therapy in RA page
Go to RA and drugs in pregnancy
Go to Methotrexate page
Go to Arava page
Go to Sulphasalazine page
Go to anti TNF drugs


drdoc on-line
March 2000
Rheumatologist
Cape Town
South Africa
Original article - Copyright protected

Updated 2011


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