Psoriatic arthritis by drdoc on-line
 
 

Psoriasis is a relatively common skin condition characterized by increased turnover of the skin to produce plaques of keratinized scales and nail changes.
Common skin sites include the flexures of the knees, elbows, umbilicus, behind the ears and at the scalp lining - anteriorly and posteriorly.
Nail changes include pitting and ridging of the nails and are common.

Less widely known but well described is the association of arthritis with the psoriasis.
In fact 5-8% of psoriasis patients develop an arthritis.
The arthritis is preceded by the rash in 70-80% of cases, but in 10 % precedes the rash.
The delay in developing the rash may be months to years. In approximately 15% the rash and arthritis appear at the same time.
The severity of the rash does not mirror the severity of the arthritis and a flare of the rash does not necessarily coincide with an arthritis flare.
Nail changes are present in 80% of patients with the arthritis versus 20% without arthritis.

The arthritis is usually seen at age 30-40ís, but it can rarely be seen in juvenile patients.
There is no sex difference in incidence.

There are five varieties of the arthritis but overlaps can occur.

1. Peripheral type - involves the distal interphalyngeal joints. 10%
2. Peripheral symmetrical polyarthritis - Similar to Rheumatoid arthritis. 25%
3. Asymmetrical joint type - asymmetrical, pauciarticular and affecting the hands, and feet, with sausage like digits. Large joints can be involved as an oligo/pauciarticular arthritis 80%
4. A spondyloarthropathy - affecting spine and sacroiliac joints. 5%-20%
5. A severe mutilating peripheral type - Arthritis mutilans.

Enthesitis - inflammation of tendon insertions occurs commonly, i.e. Achillesí tendonitis.
The sausage like swelling of the digits is a common characteristic manifestation of the arthritis and is caused by dactylitis. These can be seen also in reactive arthritis.

Family history is common and should be specifically asked for by the practitioner - especially as the rash may not be present and the arthritis may appear initially as an unspecified arthritis with Rheumatoid factor negative. The suspicion of a Psoriatic arthritis would then be considered.
The genetic HLA associations include For Psoriasis alone :A1, B13, B17, Cw6. For Axial involvement - spinal type - B27, B38. For erosive disease : DR4.

Systemic involvement can occur with:

Ocular changes in 30%
Conjunctivitis
Episcleritis
Keratoconjunctivitis sicca

Aortic Valve disease has been described.

Because of the high skin turnover - hyperuricaemia and gout can occur coinciding with the psoriasis.

Association with HIV infection is also more recently identified with a tendency to severe rash and arthritis.

Investigations

Hematology.

Elevation of the ESR and CRP are proportional to the inflammatory process of the disease.
Rheumatoid factor is negative, but in a small percentage of the population may be elevated in an unrelated and coincidental manner.
Therefore diagnosis of Psoriatic arthritis must be made in these patients only with caution.

Radiology

Several characteristic findings are seen on XRAY.
Asymmetrical joint involvement.
Marginal erosions.
Widening of the joint margin
Erosion of the distal tufts of the digits
Subchondral erosions and development of the pencil in cup deformity
Periostitis
Osteolysis of the bone with telescoping of the digits.
Calcification of the enthesitis points with spur formation.
Sacroiliitis in some patients - often asymmetrical.
Syndesmophytes as in spondyloarthropathies.

Therapy

The therapy is based on the principal of symptomatic relief, and consideration for second line therapy. Symptomatic therapy is similar in many respects to that of the other inflammatory arthropathies, with the exception that oral steroid / cortisone is not recommended. Concern is also raised by dermatologists that steroid withdrawal may precipitate a severe skin manifestation of psoriasis - called pustular dermatitis.

Antiinflammatories remain the cornerstone of therapy and a wide assortment of these are available, and choice as to which type can be individually assessed. Analgesics for pain relief are also indicated as appropriate.

Local steroid injections ie.. triamcinolone are extremely useful for therapy of both Articular and soft tissue lesions - such as bursae, and tendonitis.

Joint protection and physical and occupational therapy are essential aspects to treatment and maintenance of function. Adequate splinting of joints - ie semi-static resting splints for the wrists ( my favorite splint here is the Futuro wrist splint), are very useful to reduce swelling and preserve function. Hydrotherapy / aquatherapy are also useful as are exercises and general rehabilitation exercise principals - determined at an individual level.

Second line therapy / Disease modifying therapy.

The choice of a second line agent is used for:
Those patients in whom the skin disease itself is severe.
Where the extent of arthritis is severe.
Erosive disease.
The function of the patient is threatened.
Symptomatic or conservative therapy is not sufficiently successful.

The choice of agents

1. Methotrexate. This is increasingly seen world-wide as the agent of choice, with starting dose 7.5 - 15 mg./ week Caution is raised regarding hepatotoxicity, and monitoring is essential. The skin and joints are shown to benefit - usually from the 2nd - 3rd week of therapy. Dose can be increased if required up to 20-30mg / week.

2. Gold Salts - either oral or injectable. This generally helps 50-75 % of patients

3. Salazopyrine (Sulphasalazine) This I find extremely useful for the spondyloarthropathy in particular, but benefit to the arthritis as well as to the skin manifestations are reported in several studies. The dose is 1g twice daily.

4. Antimalarials are generally not used as they are frequently identified with a deterioration in the psoriasis.

5. Retinoids i.e. etretinate are used mainly for the psoriasis rash, but have been shown to also relieve the arthritis. However they have a high side effect profile and can cause teratogenicity, making their use difficult in a population of patients in childbearing years. They also interestingly have been associated with development of a hypertrophic skeletal spinal disorder - DISH - diffuse idiopathic skeletal hyperostosis.

6. Cyclosporine A has also been used in resistant cases at 5mg / kg / day , with improvement at 2-4 weeks. The arthritis and skin, benefit but the disease activity returns within 6 weeks of drug withdrawal. The drug needs monitoring because of hypertension and renal problems.

7. PUVA - Photo chemotherapy (Psoralen Ultraviolet A, PUVA) PUVA treatment is of benefit for some Psoriatic arthritis patients. This benefits skin and was shown to help the peripheral ( but not the axial ) arthritis as well.

Biologic drugs

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

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.

No trials available yet in Psoriasis

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

No trials available yet in Psoriasis

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

No trials available yet in psoriais

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.

Surgery

The use of surgery may be required in the event of joint mechanical changes and the principals of surgery are the same as for Rheumatoid arthritis.

The use of these drugs and therapeutic options requires experience and understanding of the potential complications. Therefore Rheumatologist involvement should be strongly considered.

 
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Dr David Gotlieb
MBChB FCP(SA)
Rheumatologist
Cape Town
South Africa.
Nov. 1998
Original Article-copyright
Revised Oct 2010