Treatment of Rheumatoid Arthritis and Osteoarthritis.
A Guide to the General Practitioner / Family Physician
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The assessment of any arthritis disease requires clarification of the specific disease as well as assessment of the stage, activity of the disease and an assessment of function. In doing so one can assess prognosis. Thereafter therapy is aimed at symptomatic therapy, specific disease modifying therapy and rehabilitation with restoration of function.
Non-pharmaceutical therapy is applicable as an essential part of treatment, and a multidisciplinary approach is ideal. This encompasses physiotherapy, occupational therapy and education, aimed at empowering the patient to understand all aspects of a chronic disease process.
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  Osteoarthritis (OA) is perhaps the model degenerative disease, whilst Rheumatoid Arthritis (RA) is a classic inflammatory arthritis. Both diseases warrant symptomatic therapy, consisting of anti-inflammatory therapy and analgesic therapy. However, in addition, a disease modifying approach is applicable to both diseases, particularly for RA, where it is now demonstrated to have revolutionised treatment and improved outcome in patients.    
  Ideally, treatment of these diseases should occur by or in consultation with a rheumatologist, but this is not always possible for logistic reasons. The General Practitioner should be seen as part of the team, and should endeavour to acquire skills of diagnosis, and a sound understanding of disease modifying drugs and their potential side effects, and requirements for monitoring.    
 
Non pharmacological therapy

This is provided by Physiotherapists, Nurses, Educators, Occupational therapists, Orthotists, Dieticians, Social workers, and the families and patients themselves.
The Physical Therapist plays a 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 includes resting or immobilising acutely inflammed joints, and maintaining joint range of movement by active movement and passive stretch exercises. Heat, laser and ultrasound provide relief to the soft tissues. Hydrotherapy plays role in mobilising and provides exercise in a non-impact, buoyant environment to restore muscle tone and power. As the joints become less inflammed, movement is encouraged with active exercises against progressive resistance.
The Occupational Therapist looks at the function of the patient in the context of their disability. They teach and provide joint protection advice. They provide assistant devices and splints. Resting Splints are used during acute phase and thereafter, serial splints are used with semi-static, resting splints progressing to dynamic splints. The use of assistant devices and education about the activities of daily living is invaluable.
The Dietician provides advice regarding a balanced diet and weight control, a major problem especially in disease of large weight bearing joints, especially in OA. There is no specific diet for arthritis. Red meat is reduced and fish and vegetable intake is encouraged. In some patients aggravation by certain foodstuffs may be noted and advice is given to avoid these in individual cases.
The Orthotist provides a vital service especially by providing orthotics, such as arch supports for ankle and subtalar disease and metatarsal domes for metatarsal disease.
   
 
Pharmacological Therapy

Symptomatic therapy is useful to relieve discomfort. However, other than helping to maintain mobility and joint range of movement, it has no influence on actual disease control or influence on outcome. Analgesia was previously seen as first line therapy in disease, but recent advances have changed the classical teaching. In RA, the early use of disease modifying drugs (DMARDs) have changed disease outcome. It is not considered sufficient to treat RA with analgesics or anti-inflammatories alone. In OA, the first line approach of analgesics has also been challenged. Evidence suggests that OA is a heterogeneous condition with significant inflammation present, and not a simple mechanical or degenerative disease. Evidence suggests that anti-inflammatories are more efficacious than analgesics in OA. Previous guidelines for therapy of OA, advocating analgesia as first line have been heavily influenced by the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The advent of specific COX-2 inhibitor drugs have made effective, safer, use of anti-inflammatories possible, even in the higher risk elderly patient population seen in OA.
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Analgesia.
Analgesics are used in a stepwise fashion, titrated according to severity of pain. Mechanical problems are worse through the day and with activity, and analgesics may be used "as required". They include Paracetamol, Paracetamol-codeine combinations and stronger medications such as Tramadol and Dextropropoxyphene. Advantages of the analgesics include relative sparing of gastric ulceration, but increasing problems with constipation as well as renal and hepatic impairment.
Anti-inflammatories.
These include the older non specific COX inhibitors and the newer COX-1 sparing, COX-2 specific drugs which provide an increased safety profile, by sparing the stomach mucosa, reducing ulceration, and also maintaining platelet function. Anti-inflammatory drugs are best used in patients who are manifesting symptoms of inflammation: Swelling, stiffness and local heat in the joints.
The concern that NSAIDs damage human cartilage is not confirmed, although indomethacin may accelerate deterioration in OA of the hip.
COXIB drugs, including Celecoxib (Celebrex), and Etoricoxib (Arcoxia),, are more expensive than old non specific NSAIDs, but have been shown to be less toxic to the gastric mucosa. They constitute a whole new class of NSAIDs. They have altered the approach to early use of NSAIDs as analgesic therapy, especially in at risk population groups, such as the elderly, precious peptic ulcer disease and co use of corticosteroids. Unfortunately, health funders, perhaps inappropriately, see these as too expensive for general use. However complications, including bleeding and transfusion requirement, are reduced. In addition, the platelet sparing effect, make their use in the perioperative environment much more desirable than the older NSAIDs which were associated with increased bleeding and haematoma formation. Because osteoarthritis occurs in the more elderly, COXIBS allow safer early use of anti-inflammatory therapy. Rofecoxib, (Vioxx), however, a Coxib has been voluntarily withdrawn by Merck due to increase in myocardial infarction noted in some studies. COXIBs are not cardioprotective and therefore co-prescription with low dose aspirin is important in individuals with cardiovascular risk.
Other strategies to reduce gastric side effects of older NSAIDs, include co-use with proton pump inhibitors, or misoprostol. Some of the older NSAIDs, including meloxicam, diclofenac and ibuprofen, have a more selective COX 2 to COX 1 ratio, than other NSAIDs such as piroxicam or ketoprofen. They are however NOT specific COX 2 inhibitors.
 
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Disease modifying drugs.
In Rheumatoid arthritis, there is a now recognized requirement for disease modifying drugs early on in the disease. In fact Rheumatologists now support the use of DMARDs as soon as the diagnosis is made. The concept of the pyramid approach to therapy (Fig. 1.) is no longer applicable in RA, and the pyramid approach is now inverted.
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  DMARDs are used either alone or in combination. Some Rheumatologists advocate a step up approach, adding or replacing should response be incomplete. The aim is remission of disease. (Table 1, 2) This is however only rarely achieved although help is obtained by amelioration of disease in the majority. Evidence suggests that even short term exposure to DMARD will improve long term prognosis.
Rheumatologists advocate ongoing DMARD, as long as there is no side effect and as long as there is continued efficacy. Stopping the drugs will result in inevitable recurrence in the majority, in approximately three weeks. Patients are advised NOT to stop their medication.
There is a rank order of efficacy (Table 3), and generally, stronger drugs have a greater side effect profile. Side effect and monitoring is therefore drug dependant. In practical terms the gold standard DMARD is Methotrexate, but most Rheumatologists also use Sulphasalazine and Antimalarials (Hydroxychloroquine, Chloroquine sulphate, Chloroquine phosphate).
Gold and Penicillamine are not frequently used any longer, due to toxicity profile.
Newer DMARDs now developed include Leflunomide (Arava).
For resistant disease, drugs such as Azathioprine or Cyclosporine were used in the past, but biological agents against cytokines, especially tumour necrosis factor, and IL-1, which promote disease, have been developed. Anti TNF agents include Etanercept (Enbrel), Infliximab (Revellex, Remicaide) and Adalimumab.(Humira) These have provided dramatic advance in treating resistant disease, but are limited by cost and risk of side effect, especially reactivation of Tuberculosis. Other biological therapeutic agents include RoActemra Tocilizumab, Mabthera (Anti CD 20 B cell inhibitor, Orencia (Co stimulatory molecule inhibitor), Anakinra (IL-1 receptor antagonist). These drugs should remain for specialist usage.
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Classic DMARD drugs in RA

1. Methotrexate

Methotrexate is given as an injectable or oral preparation. It is used at night and the usual recommended starting dose is 7.5 - 10 mg per week and increasing dose versus response to 20 mg / week. The drug takes approximately 4-6 weeks for a response to start.

It cannot be used in established or active liver disease, renal impairment, significant lung disease and excessive alcohol abuse. A history of hepatitis should be established prior to therapy.
A chest X-ray should be performed at start of therapy

The side effects include nausea, diarrhoea, rashes, alopecia, mouth ulcers and stomatitis.
More severe effects include marrow suppression, liver toxicity and pulmonary toxicity (pneumonitis). To prevent nausea, doses should be administered in the evening.
Urine analysis is required every 3-6 months.

The use of folic acid with the drug is used to reduce side effects. In South Africa, common practice is to use 5mg per day. Use of folic acid does not interfere with drug activity and is given daily.
Liver biopsy is not considered essential for baseline assessment or for routine follow up after a predetermined total dose. Guidelines are now available for follow up and need for biopsies.
Routine monitoring must be done using blood count and liver function assessments -- AST, ALT, GGT and full blood count. Blood tests must be done at baseline, at one month, and thereafter every 2 months. If levels are persistently increased 50% above normal, consider biopsy if the drug is to be continued.

Pregnancy: Teratogenicity is reported and therefore, males and females on methotrexate should be taken off the drug for 3 months before conception. The drug is also contraindicated in lactation.

 

2. Sulphasalazine

Sulphasalazine consists of two agents - a sulphur (sulfapyridine) and a salicylate component, 5 amino salicylic acid. The drug is introduced slowly over the first month to avoid problems of nausea and gastrointestinal irritability - starting 0.5 g daily for one week, then 1 g daily for one week, then 1.5 g daily for one week, and thereafter 2 g per day. Response takes between 1-6 months.
Adverse events are reported more in the first three months of use and have a generally low profile with no long term effects reported. The drug is generally well tolerated. Dose reductions are usually effective for minor side effects.

Mild side effects include:

 Gastrointestinal discomfort, with nausea, vomiting, loss of appetite, abdominal pain.
 Skin rashes and allergic manifestations are common.
 Headaches, mood alterations.
 Reduced sperm counts may be seen but this is reversible.

Rare severe problems requiring drug withdrawal include:

 Marrow suppression.
 G-6-PD deficiency related anaemia with haemolysis.
 Nephrotoxicity.
 Hepatotoxicity.
 Pulmonary toxicity.
 Major allergic rashes - including Stevens-Johnson syndrome

Monitoring requires baseline blood count and liver function assessment including especially AST, ALT, GGT and Urine analysis. The monitoring must be done monthly for 3 months and then every three - six monthly.
Pregnancy: No teratogenicity is reported from over 2000 reports of pregnancy on the drug, mainly in inflammatory bowel disease patients, but it is generally advised that the drug be discontinued in pregnancy unless considered essential because of severe disease. The drug is considered safe in lactation, with little sulphasalazine in the milk, and sulfapyridine levels 40% of plasma levels.

3. Antimalarials

These are Chloroquine salts / Hydroxychloroquine. They are generally seen as milder drugs.
The use of Chloroquine is generally for milder disease or in combination therapy and it takes about three to six months to demonstrate efficacy. Hydroxychloroquine has on meta-analysis review been shown to be slightly weaker, but less side effect prone than Chloroquine.

Side effects:

Minor side effects include:
Nausea.
Rash and photosensitivity. Skin pigmentation in sun-exposed areas may develop.
Diarrhoea
Neuromyopathy is reported rarely.

Serious side effects:
The main problems are ophthalmological. Prolonged therapy has been associated with fundal defects with maculopathy, especially peripheral vision and reduced night vision. Therefore regular ophthalmological assessment is required on a six monthly to yearly basis. Baseline assessment is required within the first six months. Early examination may reveal dose related corneal deposits, necessitating dose reduction. Retinal changes are a consequence of excessive daily dose and not thought to be from accumulation.

Dose recommendations - Chloroquine - 4mg / kg. Hydroxychloroquine - 6.0-6.5 mg/kg.
These are calculated on the amount of chloroquine base in the drug. Dose reductions must be considered in the elderly. Once stabilized, dose reductions can be considered by reducing frequency of administration.
It is advised that the drug be taken with food to improve bioavailability and reduce nausea.

Monitoring - regular 6 - 12 monthly eye checks for field-testing.

Pregnancy:
Little information is available, as fewer than 100 reports exist of pregnancy in rheumatoid arthritis patients on antimalarials. However, amongst these there are no reports of adverse fetal effect, and therefore the advisory, is that the drug should be stopped, unless absolutely necessary.

4. Minocycline

Antibiotic therapy especially Minocycline has been controversial but some studies now suggest that there is a response to Minocycline. It is seen as an option in milder disease.
Trials have been contradictory but the balance of early trials showed benefit. Radiological progression has not been slowed by use of the drug.

Dose recommended is 100mg twice a day.
Effectiveness takes approximately 3-6 months.

Side effects:

 Nausea, vomiting, taste disturbance in 30%.
 Hyperpigmentation and tooth discoloration.
 Skin rash, photosensitivity.
 Headaches.
 Hypersensitivity pneumonitis.
 Hepatotoxicity.
 Drug induced SLE and Antinuclear factor (ANF) positivity.

Pregnancy and lactation: contraindicated.

5. Leflunomide (Arava)

This is metabolized to active metabolites that inhibit dihydroorotate dehydrogenase. This is the rate-limiting enzyme in pyrimidine nucleotide synthesis. In Rheumatoid arthritis, the activation and proliferation of T cells is therefore impaired. Clinical trials show reduction of joint counts and improvement of physician and patient global assessment, with improvement in function. Trials suggest efficacy is sustained. Comparison with Methotrexate suggests equivalent efficacy, and improvement compared to placebo. There is also evidence for reduction in erosions. Trials are ongoing regarding combination therapy, including with Methotrexate.

Side Effects:

 Gastrointestinal symptoms, diarrhoea.
 Skin rash
 Alopecia (reversible)
 Elevation of liver enzymes
 Severe teratogenicity.

Serious adverse events in trials are seen in approximately 20 % of patients, requiring stopping the drug in 15% of patients. Drug levels can be reduced or eliminated, if side effect, by use of cholestyramine.
Pregnancy is absolutely contraindicated (for male and female patients) and there is a minimum three year recommendation off the drug before initiating a pregnancy. Alternatively the drug can be eliminated, but the drug level should then be measured to ensure complete elimination prior to stopping contraception.

Systemic Corticosteroids

These have their place in inflammatory arthritis, in low dose in articular disease but in high dose for systemic extra-articular involvement of RA.
For Articular disease the dose should be kept low at or below 7.5mg per day of prednisone. It should be taken in the morning. Alternate day use is not well tolerated by RA patients, as the disease is sensitive to small changes in dose.
They are particularly useful for the stiffness and swelling whilst DMARDs are being initiated and prior to effect. Thereafter the prednisone should be reduced and possibly stopped where possible, over 2-3 months.

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DMARD therapy in Osteoarthritis

Tremendous research is ongoing in Osteoarthritis, and the disease is seen as several subcategories including an inflammatory subtype associated with early onset, genetic background and swelling and soft tissue component on examination.

Glucosamine Sulphate

There is some accumulating evidence that Glucosamine sulphate has efficacy in Osteoarthritis, with trials showing pain relief but also chondroprotection. Three and five year follow up in patients treated for osteoarthritis of the knee, show a slight increase in joint space, compared to loss in placebo groups. Glucosamine sulphate is made from shrimp and crab shells and consists of the building block of the glycosaminoglycans, the ground substance of cartilage. It has been shown to increase proteoglycan synthesis. It is absorbed well and is excreted in lung and kidney. The recommended dose is 1500mg / day. The consumer is faced with a large choice of product. Unfortunately there is no quality control regarding of the bioavailability of the active ingredient. Importantly, most studies showing efficacy are based on the SULPHATE moiety, and there is no evidence that the CHLORIDE product is as efficacious. Similarly, studies of Chondroitin Sulphate are not definitely conclusive and this constituent derived from bovine sources, adds considerably to the price.

Diacerhein

This is a compound derived from Rhubarb and is the acetylated form of anthraquinone, Rhein. The drug has been shown in some trials to reduce symptoms as well as reduce the inflammatory response of IL-1 in chondrocytes. There is evidence that it may reduce cartilage loss in OA of the hip, compared to placebo. The product is not yet available in South Africa.

Other disease modifying therapies in OA

Trials of Tetracycline and Antimalarial therapies are in process. Tetracycline blocks synthesis of nitric oxide as well as blocking metalloproteases involved in cartilage destruction.

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Intraarticular Injections in RA and OA

Corticosteroid Injections

If a joint is swollen and out of phase with the rest of the disease activity, then it is frequently useful to inject that joint directly. Joint injection techniques require skill and should be done as a sterile, non-touch technique in the clinic setting. They should NOT be painful. A painful injection may suggest the injection has been incorrectly administered. Similarly, tendon and soft tissue injections are very useful, but require precise diagnosis and anatomical location of the abnormality.

Whereas systemic corticosteroid has little place in OA, there is no doubt that intraarticular steroid helps symptoms in patients with OA. However, the benefit is short lived lasting weeks to months.

Side effects other than infection are mild, with flushing, skin discolouration and local fat atrophy, especially if the injection is misplaced. Diabetic control may also require monitoring.
Injections should be limited to 3-4 times per year in weight bearing joints. They must be an adjunct to control of the underlying disease.

Hyaluronan

This is given as an injection into the joint, of linear glycosaminoglycan. It supplements endogenous hyaluronan, which is reduced in the OA joint. It is made from Rooster comb, with chemical modifications to increase half life and increase claimed efficacy. It does not work as a simple lubricant, as it is cleared rapidly from the joint. Action is more by influence on synovial cytokines. The trials do not show definite long term efficacy, and widespread use is not justified. However some patients do see benefit in symptom relief lasting months. They therefore may have a role in patients who require but do not want surgery and fail to respond to corticosteroid injection.

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Surgery

Surgery plays a special role in patients who have mechanical joint problems that impair daily life and are not responding to medical and conservative therapy.

The advent of replacement arthroplasty (joint replacement), has been a major advance in the treatment of Rheumatic disease. Survival rates of Total hip replacement (THR) and Total Knee replacement (TKR), is 10-15 years. Age is not a contraindication to surgery. Anaesthetic techniques and anticoagulation have reduced perioperative complications. Late complications include Infection, loosening, osteolysis, periprosthetic fracture and wear of the prosthesis.

Timing of joint replacement therapy is delayed until conservative therapy fails. However, if there is a problem of regional osteoporosis and loss of bone stock, delay may be harmful in some patients.
In addition, it is important to address the underlying disease, especially in RA, as active disease will limit rehabilitation.

Arthroscopy has also been revolutionary in management of internal derangements to the joints, especially relating to meniscal tears and foreign bodies in the knee. Other forms of arthroscopic lavage and debridement of osteoarthritis joints however are more controversial and recent trials show no benefit from this procedure.

Decisions regarding surgery must have appropriate indications, and whilst it may offer a quick solution, surgery should be considered an adjunct to medical therapy and not a replacement for medical therapy.
Chondral defects can also be managed arthroscopically using osteochondral autografts or by cartilage cell transplant or periosteal grafts, both of which are performed in open surgery. However these remain experimental rather than for general application at this time.

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Recommendations for South African primary care practitioners for use of DMARD in RA: Summary

1. Confirm the diagnosis as early as possible. Whilst classification criteria exist, these are NOT diagnostic criteria. (Table 4)
2. Assess degree of activity by assessing degree of stiffness and swelling / joint counts.
3. Assess risk factors. (Genetic subsets with HLA typing especially shared epitope identifies severe disease and has been used by O'Dell to predict the response to combination therapy. However, this is not felt to be practical for the South African situation.) (Table 5)
4. Monitor the patient for efficacy and side effect. (Table 6)
5. Refer where possible to a Rheumatologist or Specialist with an interest in Rheumatology. Encourage a team approach with the specialist

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A personal recommendation for DMARD use

Early active disease presenting with symptoms / features of rheumatoid arthritis but little synovitis on examination and low risk factors: suggest management with COXIBS / NSAIDs and consider early introduction of disease modifying therapy if still active at three months after onset of symptoms: Recommendation to start Sulphasalazine or Hydroxychloroquine. If inadequate response or progression by one to three months on DMARD, add methotrexate.

Early active disease presenting with features of rheumatoid arthritis with mild to moderate synovitis and risk factors: suggest management with COXIBS / NSAIDs / low dose steroids with introduction of methotrexate. If inadequate response by three months: add a second disease modifying drug - Sulphasalazine or Hydroxychloroquine.

Early active disease presenting with features of rheumatoid arthritis with moderate to severe synovitis: initiate dual therapy early in combination low dose Corticosteroids. Dual therapy includes methotrexate with Hydroxychloroquine or Sulphasalazine. Specialist referral desirable.

Early active disease presenting with features of rheumatoid arthritis with severe synovitis and risk factors: initiate triple therapy early in combination low dose Corticosteroids. Triple therapy includes methotrexate with Hydroxychloroquine and Sulphasalazine. Specialist referral desirable.

Intolerance to Methotrexate but normal liver function, consider Leflunomide. However this requires specialist referral.

If established rheumatoid arthritis not responding or intolerant to triple therapy: consider the use of Leflunomide, and if still no response consider Azathioprine. Specialist attention considered mandatory.

Established rheumatoid arthritis not responding to any therapy -- consider Etanercept / Infliximab Adalimumab / Biologic - depending on availability. Other biologics for RA first line include RoActemra. Specialist attention considered mandatory.

Remember - all patients require individualized therapy, and this article provides a guideline. Where possible, referral to a Rheumatologist is strongly recommended.

 

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Table 1: Goal of therapy
1 Reduction of pain
2 Reduction of inflammation
3 Prevent join destruction
4 Preserve of joint function
5 Return to a productive life
6 Remission
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Table 2: Criteria for remission
1. Duration of morning stiffness not exceeding 15 minutes.
2. No fatigue.
3. No symptoms of joint pain.
4. No joint tenderness or pain on motion.
5. No soft tissue swelling in joints or tendon sheaths.
6. ESR < 30 (female) and <20 (male)

NB Require 5 or more for at least 2 consecutive months. There must be no clinical manifestation of active vasculitis, pericarditis, pleuritis, or myositis or unexplained recent weight loss or fever attributable to rheumatoid arthritis.

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Table 3: Relative strengths of DMARD.
Drug strength - Rank order: Weak to Strong
1. Auranofin (oral gold)
2. Hydroxychloroquine /Chloroquine Minocycline
3.
Sulphasalazine / Intramuscular gold / D-Penicillamine
4.
Methotrexate / Leflunomide
5. Biologic drugs
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Table 4: 1988 revised ACR criteria for classification of RA: Arnett FC, Edworthy SM, Block DA, et al: The American Rheumatism Association 1987 criteria for the classification of Rheumatoid arthritis (abstr). Arthritis Rheum 1987;30:S17
1 Morning stiffness greater than 1 hr greater than 6 weeks duration
2 Swelling in 3 or more joints for greater than 6 weeks duration
3 Swelling MCP or PIP greater than 6 weeks duration in wrist
4 Symmetrical joint swelling
5 Rheumatoid nodules
6 Serum rheumatoid factor
7 Hand X-ray changes - erosions or decalcification
Require 4 or more for classification
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Table 5: Factors suggesting poor prognosis
1 Early age at onset
2 High titre rheumatoid factor
3 Young female
4 Elevated ESR / CRP
5 Elevated platelet count
6 Swelling >20 joints
7 Extra-articular disease
8 Shared epitope positivity - HLA-DRB1 typing
9 Radiological detection of erosions
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Table 6: Measurement of response to therapy
1 Duration of morning stiffness
2 Severity of fatigue
3 Joint swelling scores (tender / swollen joint counts)
4 Visual analogue scores for pain and stiffness.
5 Physician assessment visual analogue scores.
6 Evidence of disease progression on examination - loss of motion / deformity
7 Patient global assessment visual analogue scores.
8 Basic functional assessment scores- in particular the Stanford health assessment questionnaire - HAQ score.
9 ESR, CRP, platelet count
10 Radiological damage
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Fig 1. Old pyramid guide to therapy of RA.

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  Fig 2: Early RA showing soft tissue swelling

Fig 3: Damage from chronic Rheumatoid Arthritis

   
       
 
Fig 4: Osteoarthritis - bony thickening of heberden and bouchard nodes


   
  Dr David Gotlieb
Rheumatologist
Constantia Arthritis Clinic.
FCP(SA)
Jan 2005 Revised 2011

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