Spondyloarthropathy by drdoc on-line

Index

General :The Spondyloarthropathies
Pathogenesis of the Spondyloarthropathies
Genetics
Causative Organisms involved
Ankylosing Spondylitis
Ankylosing Spondylitis - Diagnostic Criteria
Ankylosing Spondylitis Therapy
Ankylosing Spondylitis Therapy - biologics
Reactive Arthritis
Reiter Syndrome
Enteropathic Arthropathy

Ankylosing Spondylitis
Reactive arthritis
Reiter Syndrome
Enteropathic Arthritis
Psoriatic spondyloarthropathy

The Spondyloarthropathies are a group of disorders that share certain characteristics :

1. Arthritis - including peripheral arthritis and spinal involvement, usually involving also the sacroiliac joints.
2. They are Seronegative for Rheumatoid factor.
3. They may be involved with other medical problems -

including...
Psoriasis.
Inflammatory bowel disease- ulcerative colitis or crohns disease.
Post infective or reactive -to urogenital or gastrointestinal infections.
Overlaps of these disorders may be seen.

 

A strong genetic association with Class 1 HLA B27 gene (on chromosome 6) is described.

Clinically they present with swelling of joints or an enthesopathy - inflammation of tendon insertions into bone. There is pain swelling and joint stiffness. The joint distribution depends on the subtype of the disease. Spinal involvement is characterised by sacroiliitis and inflammatory back pain. The latter consists of pain stiffness and progressive spinal restriction.
The Stiffness occurs early in the day on waking and eases off through the morning. The duration of the stiffness is proportional to the activity of inflammation.
The restriction of the spine is in all 3 planes of spinal mobility -
Antero - posterior.
Flexion/extension.
Lateral flexion.
Rotation
Extra-articular manifestations may occur - including:
Skin rashes
Eye inflammation - especially uveitis.
Lung involvement
Cardiac involvement - with aortic valve disease.

Pathogenesis
Hereditary factors are noted and there is a possibility of different variants of these syndromes, occuring within families.
Pathogenesis is felt to be related to an autoimmune phenomenon - with molecular mimicry.
There is a cross reaction between an environmental and the bodies’ own tissues.
The environmental agent is thought by many to be an infective organism.
This in fact is identified in certain subsets of the spondyloarthropathies, and these subsets are called REACTIVE arthropathies. The organisms include
Chlamydia - usually from urogenital source.
Streptococcus - from airway / respiratory / skin infection, source
Yersinia,
Campylobacter,
Salmonella,
Shigella - from bowel source.
Klebsiella - from bowel source.

In fact the infection precedes the arthritis by several weeks, and it is thought to be a post infective phenomenon, rather than direct infection, that causes the arthritis.
In most cases however there is no identification of the original infective organism.
I hypothesise a genetically prone individual, whose immune system renders one unable to clear an infective organism adequately. Once exposed to the body’s immune system, the macrophages identify the organism as foreign to the body and internalise the organism by a process called phagocytosis. The macrophage processes the organism with enzymes and displays particles of the organism on the cell surface - enabling the T lymphocytes to recognize these particles and hence - resulting in the cascade of immune events that follow. Usually, the original organism is obliterated, but perhaps the continued display of antigen at the cell surface, or perhaps re-exposure by reinfection, can result in the reactivation of the immune response. Each reinfection leaves a population of “memory” T cells, that magnify the responses. Perpetuation of the response may also occur as a result of persistent hidden infection, possibly within the macrophages, by as yet unidentified organisms. The organism may be INTRACELLULAR within the macrophages and hence shielded from most of the bodies defence mechanisms, and thus never cleared.

Therefore the body sees the presence of the agent and tries to mount an ineffective but aggressive immune response. The continued exposure of the antigen from such an organism, results in a autoimmune problem by molecular mimicry, rather than direct infection. ie - the particles of the agent (the antigens )-RESEMBLE the tissue of the host, and therefore the host turns his/her immune system against itself.

The Gene Markers

The genetic markers are identified in many of these arthropathies as associated with the B27 tissue type.
The associations with the B27 and diseases vary to a degree
In The Northern hemisphere, the B27 tissue type is seen in 6-14% of the population.
The more north geographically, greater the incidence of B27 positivity.
2-10% of these B27+ve people develop one of the spondyloarthropathies.
A first degree family history of a B27 related disease increases the risk to 10%

Incidence of B27 positivity amongst Spondyloarthropathy Patients.

Disease

Percentage B27 positive

Ankylosing Spondylitis 90%
Reiter Syndrome 90%
Psoriatic arthropathy 20%, but 50% with Sacroiliitis
Intestinal arthropathy 5% but 50% with Sacroiliitis
Juvenile Ankylosing Spondylitis 90%
Reactive arthropathy 90%

The Infective Agents

Several studies are reporting the presence of infective organism DNA markers in the Synovial tissue membrane and fluid cells, using DNA chain polymerase chain reactions.
Attempts to culture the organisms have failed.
The organisms implicated are:

Chlamydia
Neisseria
Yersinia
Salmonella
Shigella
Campylobacter

They share several properties :

All cause mucosal ulceration.
Antibodies against them are synthesised on the mucosal areas.
All have lipopolysaccharide content in the outer cell membrane.
All live intracellularly - which can contribute to persistence of infection.
The cell mediated response by T cells is also demonstrated to be weaker in these patients, again possibly contributing to persistence of infection.
Chlamydia, Yersinia and Salmonella, can infect epithelial cells and macrophages.

The big question is - Is it persistent antigen from destroyed organism, or persistent infection of viable organism. Live bacteria are thought to be present in the bowel - especially for salmonella and Yersinia. This has been demonstrated on immunological staining techniques on bowel specimens of patients with Yersinia reactive arthritis. In the case of Ankylosing spondylitis (AS), there is some evidence for Klebsiella involvement. There is evidence for increased Klebsiella in the faeces of patients with AS, as well as higher antibodies to Klebsiella- especially IgA. Increased E.COLI antibodies are also noted. The use of Sulphasalazine in these patients has been shown to reduce the Immunoglobulin levels to E.COLI and Klebsiella. Interesting studies in mice which are genetically engineered to have the B27 tissue type, have been shown not to develop arthritis, if kept in germ free environments, but develop arthritis if the normal environment is restored.


Ankylosing Spondylitis.


This is an arthritis characterised by an arthritis of the sacroiliac joints and the spinal ligaments, leading to progressive, ascending spinal stiffening and spinal ligament calcification, with characteristic radiological findings.
The condition also causes, peripheral arthritis, enthesitis and extraarticular manifestations, including, pulmonary, cardiac and ocular involvement.

The disease occurs in males and females.
It used to be considered a male disease, but research has shown females to be almost equally affected, although, generally milder.
The mean age of onset is at age 27, with inflammatory back symptoms:
Pain
Stiffness and progressive spinal restriction.

The Stiffness occurs early in the day on waking and eases off through the morning.
It is improved with exercise.
The duration of the stiffness is proportional to the activity of inflammation.

Complaints of fever, fatigue and weight loss are common.

Onset is usually slowly progressive.

The diagnostic terminology of Ankylosing Spondylitis has tended to be replaced by spondyloarthropathy, as development of other associated problems, such as psoriasis, bowel or urogenital features, can present in later years. However, in the absence of these, a diagnosis of primary Ankylosing spondylitis is often referred to.

Diagnostic criteria for Ankylosing Spondylitis are referred to:

THE DIAGNOSTIC CRITERIA FOR ANKYLOSING SPONDYLITIS.

1. LIMITATION OF MOTION OF THE LUMBAR SPINE IN ALL THREE PLANES:
ANTERIOR FLEXION, LATERAL FLEXION, EXTENSION.
2. HISTORY OF PAIN IN THE LUMBAR SPINE OR AT THE DORSO-LUMBAR JUNCTION.
3. LIMITED CHEST EXPANSION TO 2,5 cm OR LESS, MEASURED AT THE FOURTH INTERCOSTAL LINE.
4. SACROILIITIS on Xray of the Sacroiliac joints.

The sacroiliitis is graded on Radiological criteria:

GRADE 0: NORMAL.
GRADE 1: SUSPICIOUS.
GRADE 2: MINIMAL ABNORMALITY, SMALL AREAS OF EROSIONS OR SCLEROSIS, WITHOUT ALTERATION OF JOINT WIDTH.
GRADE 3: DEFINITE ABNORMALITY- MODERATE OR ADVANCED SACROILIITIS WITH IRREGULARITY, ONE OR MORE EROSIONS, EVIDENCE OF SCLEROSIS. PARTIAL ANKYLOSIS
GRADE 4: TOTAL ANKYLOSIS.

DEFINITE ANKYLOSING SPONDYLITIS:

GRADE 3-4 SACROILIITIS WITH AT LEAST ONE CLINICAL CRITERION. OR
GRADE 3-4 UNILATERAL OR
GRADE 2 BILATERAL SACROILIITIS, WITH CLINICAL CRITERION 1 OR
CRITERION 2 AND 3.

PROBABLE ANKYLOSING SPONDYLITIS:

GRADE 3-4 SACROILIITIS WITHOUT ANY CLINICAL CRITERIA.

Radiological Findings

Early on, X-Rays may be unremarkable, and a bone scan (Technetium 99) may be useful to identify sacroiliitis.
Difficulties in interpreting Xray of the sacroiliac joints exist in juvenile patients, and the sacroiliac joints are uninterpretable under age 18 years of age.
Ideally, an AP view of the pelvis is all that is required, but oblique views of the Sacroiliac joints is frequently useful.

Current MRI technology is replacing Technetium scanning for assessment of the Sacroiliac joints. MRI is the best method of diagnosing / confirming sacroiliitis radiologically.

 

As the disease progresses, changes become visible on the X-Rays of the lumbar spine:

Squaring of the vertebrae
Development of bony bridges between the vertebrae - Syndesmophytes.
Calcification of the anterior and posterior longitudinal ligaments
Development of the “Bamboo Spine”

Ankylosing Spondylitis :Articular Disease

Physically the patient may have little to find early on , other than muscle spasm, but with time:

Loses the usual spinal curvature
Develops restricted range of spinal movement.

The latter is measured with the Shober test (The distraction of two specific point marked 15 cm apart on flexion of the spine). A shober test of under 6 cm is abnormal.
Thoracic chest expansion is reduced, due to involvement of the costovertebral joints. (Below 3 cm is abnormal).

Peripheral joint involvement may occur, in 30% of cases.
Hip disease is the most serious joint involved, and suggests a more severe disease.
Enthesopathy is common - especially, plantar fasciitis and Achilles tendonitis.
Costochondritis, with chest pain is common.

Over time, the patient may become more stooped and bent.
The thoracic spine becomes more kyphotic, and chest expansion reduced.
The patient may experience some breathlessness.
Neck involvement results in loss of the lordosis and as a result the patient is unable to look straight and has to elevate the eyes for forward gauze.
The hips may develop a flexion contracture, as may the knees, resulting in the classic bent posture of ankylosing spondylitis.

Ankylosing Spondylitis : Extra-articular Disease.

Eye involvement is potentially serious with uveitis. This presents as a painful red eye. Vision may be disturbed. Up to 25% may develop uveitis. The involvement occurs especially with peripheral disease, but does not reflect severity of disease. Treatment usually requires steroid eyedrops, and is usually self limiting.

Lung disease, may occur with upper lobe fibrosis, that may resemble the scarring of pulmonary Tuberculosis. Cavitation can occur of the lung parenchyma.

Cardiac disease, includes, aortic valve disease, and conduction abnormalities. Cardiac enlargement may occur.

Secondary amyloidosis is sometimes seen especially in the Northern hemisphere. In the Southern hemisphere for example in South Africa, it is exceedingly rare.

Ankylosing Spondylitis  : The Laboratory.

In fact the diagnosis is a clinical one, combined with X-ray findings.

If I am questioning the possibility of inflammatory back pain, I find a Blood Count and a Sedimentation rate (ESR), as well as the C-Reactive Protein (CRP), extremely useful.
The B27 test is not really essential, and I do not screen patients routinely for this.
The presence or absence of B27, does not confirm or exclude a diagnosis of ankylosing spondylitis.

Ankylosing Spondylitis : Treatment.

Basic Approach

The treatment of Ankylosing spondylitis used to be mainly a combination of physical therapy and exercises to maintain mobility and posture. These were combined with antiinflammatory drugs to enable symptomatic relief. Education - to ensure the exercise programme continues is vital.

Exercise - should be aimed at maintaining the full spinal range of movement, and should be assisted be an experienced physical therapist. A stretch programme is essential, and an Aqua-water therapy is very useful. Swimming is to be encouraged.
The patient should sleep on a firm mattress and use only 1 pillow to avoid neck contractures.
Smoking should be avoided as the lung involvement is aggravated by the smoking, and this may shorten the life of the patient.
My choice and approach to the use of
Non Steroidal antiinflammatory drugs is available elsewhere on this website. (Click here ) In Ankylosing spondylitis, I have a preference for a nocturnal indomethacin suppository if this is acceptable to the patient aesthetically.
I also occasionally make use of a local antiinflammatory poultice.
Analgesics may be required in different strengths and preparations depending on severity of the pain.

Ankylosing Spondylitis : Second line therapy

I encourage the use of second line therapy.
Where possible, (if no contraindications), and if the disease is considered active, all my patients are commenced on Salazopyrine, (Sulphasalazine).
(Click here for the website Sulphasalazine page) My personal experience is that the drug is very useful as a “remission” drug, and I am usually able to stop NSAID’s in approximately 70% of my patients. Occasionally, if there is no response or contraindication to Sulphasalazine, and clinically active disease, I may use Methotrexate (Click here for the website methotrexate page)

The use of Antibiotic therapy, especially tetracyclines - and Minocycline in particular, have a theoretical potential place, which is unfortunately not fully substantiated at a clinical level.
My feeling is to reserve it for consideration in patients with reactive arthritis and spondyloarthropathy that is not responsive to Sulphasalazine or methotrexate.
Studies are in progress, but existing studies are not dramatically positive.

Ankylosing spondylitis: biologic therapy

Biologic therapy is the most outstanding therapy developed for Ankylosing spondylitis.

These treatments have literally revolutionized the treatment of these diseases.

Most of the trials involved the anti-TNF agents.

Not only is there a response in terms of symptoms with reduction in stiffness, but also there is evidence for repair of erosions, and halting of disease. Because of the expense of these drugs, we require patients in South Africa to fail at least sulphasalazine or methotrexate, before progressing to a biologic drug.  However, there is no doubt that the treatment of the future is going to be anti-TNF therapy.

Drugs available n South Africa for Ankylosing Spondylitis include.

REVELLEX - Remicade - infliximab.
Enbrel - Etanercept.
Humira - Adalimumab

Ankylosing Spondylitis : Biologics

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

enbrelAn 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.

Trials in Ankylosing spondylitis are awaited

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

Trials in Ankylosing spondylitis are awaited

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

Trials in Ankylosing spondylitis are awaited

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.

 

Ankylosing Spondylitis : Additional therapies

Local injections of corticosteroid preparations into large joints and sometimes into the sacroiliac joints may be extremely effective, and I use them frequently in my practice.

Diet should be aimed at moderation. There is no specific diet, but I tend to advise reduction of red meat, and increase fish and vegetable content, and fibre. If a specific food is found to aggravate the individual, I advise that individual to leave THAT food out.

Ankylosing Spondylitis : The prognosis

This is extremely variable.
Some people advance, whilst others have disease remissions with minimal deformity.
Advanced hip and knee disease may be surgically treated with joint replacement.

With ideal therapy, advanced disease and progression is reduced, through modification of the disease process and prevention of advanced spinal deformity, through education, regarding exercises and posture.


Reactive Arthritis


This refers to the development of an arthritis, in association with a recent infective episode.
Usually the infective episode occurs 1-4 weeks prior to the development of the arthritis.
The process is a sterile one, and no organism can be cultured. It is NOT a septic arthritis. In some instances, a rising titre of antibodies can be detected on laboratory investigation, and some organisms can therefore be implicated..
The commonest organisms involved are discussed above, as are the pathogenetic mechanisms.

The association with B27 tissue type is approximately 50%.

The pattern of clinical involved is usually lower limb in distribution, especially knees, ankles and feet.
The arthritis is usually asymmetrical in distribution.

The development of enthesopathy and tendonitis, especially Achilles tendonitis or plantar fasciitis is common.

Sacroiliitis is frequently demonstrated

Mucocutaneous rashes and ulceration may occur.

Extraarticular features, especially ocular, cardiac and neurological problems, are well documented and outlined above.


Reiter Syndrome. - reactive arthritis


Reiter Syndrome was first described in 1916 by H. Reiter and is the prime model of reactive arthritis. In fact the name Reiter in fact has been expunged from medical nomenclature as the man was a Nazi who experimented unethically on human subjects and the concept of Reiter syndrome now merges with reactive arthritis.

It consists of a triad of:
Arthritis.
Urethritis
Conjunctivitis.

It occurs in 2-3% of patients exposed to epidemics of bacteria known to promote Reiter Syndrome.
Overall annual incidence is approximately 30 per 100000 of a population
Males are more frequently involved, approximately 5:1.
A recent increase in incidence has been well documented in patients with HIV virus and acquired immunodefficiency syndrome (AIDS)

The syndrome usually follows an episode of Urethritis, Cervicitis, or Dysentery.
The genital source is usually associated with Chlamydia Trachomatis.
In females It may manifest as a Cervicitis or cystitis .
A discharge, usually mucoid, or burning of the urine may be the only signs. It may be asymptomatic.
Blood in the urine may be seen.
In males, there may be ulceration (usually painless) of various severity of the glans of the penis, or urethral meatus (Circinate Balanitis).
Sometimes only erythema of the glans is seen.

Bowel source is usually
Shigella,
Salmonella,
Yersinia,
Campylobacter.

Clinically, the arthritis follows about 2 to 6 weeks after the original infection.
A constitutional illness, with fever, malaise, and loss of appetite is common.

The arthritis and clinical picture is described above, and is typical of the reactive arthritis group.

The skin lesions may include ulceration of variable intensity of the oral and genital tracts.
The ulcers are superficial but then can progress to cover larger areas of the surface.
In the skin a scaly keratotic rash is well described, especially of the palms of the hands and soles of the feet.
This is called keratoderma blennorrhagica.
The lesions can sometimes resemble psoriasis, and can also involve the nails.

Ocular involvement is usually a conjunctivitis, with painful red itchy eyes. Light sensitivity is frequent.
Occasionally however the uvea may be involved, in varying depths and severity.
Episcleritis is more superficial with blanching erythema on examining the conjunctiva.
Deeper involvement with scleritis and iritis, causes a painful red eye, which does not blanch with pressure.
Corneal ulceration may sometimes occur.
The uveitis may result in visual loss.
Eye involvement may be unilateral or bilateral.

Reiter Syndrome : The Laboratory.

HLA B27 is positive in 90% of cases.
The blood count may demonstrate a high white cell count.
The ESR and CRP are usually elevated.

Reiter Syndrome : Therapy.

This is similar to that outlined for Ankylosing spondylitis (above).
There is perhaps a greater theoretical place for the tetracyclines, especially minocycline, but studies have to a certain extent been disappointing in this regard, but are ongoing.
In most cases the arthritis is transient and responds to intraarticular injection.
An anti-inflammatory drug is often required for a variable length of time.
I tend to use a disease modifying drug - either Sulphasalazine or methotrexate, for severe disease, or where short term resolution is unlikely.
Occasionally oral low dose corticosteroid (prednisone 7.5 - 10 mg/day) is required for short courses to establish control of the symptoms, where there is inadequate control of the symptoms by the NSAID’s.

Eye involvement requires an ophthalmologist, ideally, where there is uveitis involvement. Topical corticosteroid drops may be necessary.

Skin rash is treated with topical Corticosteroids.

The overall prognosis is good.
Most recover by 6 months.
Some however may “grumble on” for 12 or more months.
A small minority develop an unremitting and potentially disabling arthritis.
Recurrence is possible.


Enteropathic Arthritis - Arthritis Associated with Inflammatory Bowel Disease.


The inflammatory Bowel diseases are immune mediated disorders involving the bowel, with ulceration, and swelling of the bowel wall.
They include Ulcerative colitis and Crohns disease.
They usually present with diarrhoea, mucus in the stool, and blood in variable amounts.
Abdominal cramps are frequent.
Constitutional symptoms of malaise, fever and weight loss are extremely common.
Diagnosis is made with demonstration of inflammatory markers on the laboratory investigation, and demonstration of bowel lesions on barium Xray studies.
Definitive diagnosis requires endoscopy and tissue biopsy showing the characteristic histological changes.

Spondyloarthropathy develops in up to 20% of these patients.
Peripheral arthritis is usually lower limb, asymmetrical and is similar to that of ankylosing spondylitis, described fully above.
Sacroiliitis occurs in 20%.
More extensive spinal involvement occurs in 5%.
HLA B27 is positive in 50%

The arthritis may precede the bowel disease or occur years later.
Enthesitis is frequent, and more common that the actual incidence of arthritis itself.
There is occasionally a relationship with bowel severity and the severity of the peripheral arthritis.
The disease may result in disability, especially if the hip disease progresses.
However it is usually non destructive and frequently “migrates” from joint to joint.
There is no clear relationship between spinal disease and bowel severity.

Extraarticular involvement with eye, and Mucocutaneous involvement is fairly common.

Treatment of the joint disease is similar to that outlined above for Ankylosing Spondylitis, with a significant place for Sulphasalazine, the NSAID’s and local corticosteroid injections.

 

Psoriatic arthritis

This type of Arthritis also has a spondyloarthropathy component but is separately discussed on the website. (Go to psoriatic Arthritis.)


Go to Top of page


Return to disease page
Go to index page
Return to drdoc on-line homepage
Go to NSAIDs page
Go to Sulphasalazine page
Go to Methotrexate page


Dr David Gotlieb
drdoc on-line
Rheumatologist
Cape Town South Africa
January 1997
Original Article - Copyright protected.

Updated 2011