First line (non Biologic) Disease Modifying Drugs for Rheumatoid Arthritis.  
The First line Disease Modifying Drugs (For Biologics click here - The Biologic Drugs)

by drdoc on-line

In general the prognosis of rheumatoid arthritis was previously felt to be good, but in fact it has now been shown that rheumatoid arthritis has a significant morbidity and mortality 1,2,3 Accordingly, the practices of Rheumatologists have changed and we are now suggesting that we use disease modifying therapy early in disease. These agents are variably known as disease modifying antirheumatic drugs – DMARD’s, slow acting anti rheumatic drugs – SAARD’s, or simply as second line agents.
Studies have shown that early introduction of these drugs may be beneficial, with improvement in pain, joint scores, and disability 4. Radiological changes appear early in the course of the disease, and are associated with the extent of the inflammatory process 5,6. Early diagnosis therefore is critical. The cautious approach by doctors in using DMARD’s has largely been a fear of side effects, but it is now observed that the toxicity profile of these drugs is not worse than the Non steroidal anti-inflammatory drugs - NSAID’s so commonly prescribed (Table 1) 7

Table 1.

Relative toxicity of NSAID’s and DMARD's:
Adapted from Fries JF. Safety issues related to DMARD therapy. J Rheumatology 1990 (Supplement 25) 17:14-7

Drug

Toxicity index

Range between drugs

NSAID / Hydroxychloroquine

2.78

1.35 – 4.57

Gold / D-penicillamine

3.42

2.58 – 4.26

Methotrexate / Azathioprine

4.32

4.14 – 4.49

Prednisone

5.34

Cyclophosphamide

6.08

Therefore we now see an inversion of the "pyramid" approach to therapy, so that DMARD’s are used early, rather than later in disease therapy (Figure 1) 8,9

Figure 1.

Surveys in the USA confirm that DMARDS are being used early in disease and in 1987 showed DMARDS were used in 85% of respondents within the first 6 months of disease 10. By 1997, 99 % of USA Rheumatologists' were reported to use combination therapy 11. DMARDS should be used before development of erosive disease or deformities develop. Therapy must be initiated if the pain and synovitis persists and especially if function is compromised. Most Rheumatologists do not wait for fulfillment of the criteria for classification of RA as published by the American College of rheumatology (ACR).

Table 2: 1988 revised ACR criteria for classification of RA 12

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 Xray changes – erosions or decalcification
Require 4 or more for classification

Other factors that are useful in deciding whether to start DMARD therapy include the prediction of more aggressive disease. Some factors have been identified and can be used as factors that assist in deciding to introduce DMARD's: (Table 3)

Table 3: Factors suggesting poor prognosis 13,14,15

1 Early age at onset
2 High titer 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

Once the disease is diagnosed the agents for disease modifying therapy include:

  • Methotrexate
  • Arava - Leflunomide
  • Sulphasalazine
  • Gold -- parenteral (Myocrisin)
  • Gold -- oral (auranofin)
  • Antimalarials -- Hydroxychloroquine, Chloroquine phosphate, Chloroquine sulphate
  • Antibiotics - Minocycline
  • D-Penicillamine
  • Azathioprine
  • Cyclophosphamide
  • Cyclosporine

New agents recently introduced include:

Leflunomide / Arava
Anti TNF and other biological agents:

In addition Disease modifying therapy are increasingly recognized for use in combination therapy.

Response to Therapy:

In the past response was considered a 20 percent improvement and it has been proposed that a 50 percent response be used as the criteria for improvement. Therefore O'Dell and co-workers have suggested that all results should be measured against 50 percent response. 16 Remission remains the ultimate goal of therapy.

Table 4: 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)
Note 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.

Approximately 2/3 of patients will respond to DMARDS, but this is not predictable from an individual perspective. The main problem with the drugs is fall-off in efficacy over time and non-serious or serious adverse effects requiring drug withdrawal. Only 20-30 percent of patients on gold / sulphasalazine / penicillamine are still taking the drug by 24 months, and approximately 50% of methotrexate patients are still on the drug at 24 months. 17,18

The drugs have relative strengths and toxicity 19:

These are summarized in tables 5 and 6.

Table 5: Relative strengths.

Drug strength

Rank order

Auranofin

1

Hydroxychloroquine / Minocycline

2

Chloroquine

3

Sulphasalazine / Intramuscular gold / D-penicillamine

4

Methotrexate

4/5

Table 6: Relative drop out rates

Drug

Drop out rate

Auranofin

+

Antimalarials

+ +

Methotrexate

+ + +

D-penicillamine

+ + + +

Sulphasalazine

+ + + + +

Intramuscular gold

+ + + + + +

Measurement of Disease activity / Response to Therapy

Several mechanisms exist to assess activity and these can be used to follow up the patient to evaluate response to therapy. These are summarized in Table 7.

Table 7: 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


Table 8: 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

The Drugs


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 15 mg / week. The drug takes approximately 4-6 weeks for a response to start.
It cannot be used in established / active liver disease, renal impairment, significant lung disease and excessive alcohol abuse. A history of hepatitis should be established prior to therapy.
A chest Xray 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.20 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 has been used for many years in the rheumatic diseases and in fact was invented the 1930' s at Karolinska Institute by Prof. Nanna Svartz. It consists of two agents -- a sulfur (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. The dose can be increased to 3 g if inadequate response. An enteric form is advised to further reduce gastric side effects. A reduction in erosions has been reported with sulphasalazine 25.

Adverse events are reported more in the first three months of use and have a generally low profile with no long term effects reported 21. 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 - reversible.

Rare severe problems requiring drug withdrawal include:

  • Marrow suppression.
  • G-6-PD deficiency related anemia 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. Despite low toxicity, only 40-70% of patients are still on the drug at 2 years, and 20 % at 5 years, due to efficacy and side effect related difficulty.

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 levels22,23,24.

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. Double blind studies show efficacy in 60-80 percent of patients. There is no influence on erosion progression compared to sulphasalazine 25. Hydroxychloroquine has on meta-analysis review been shown to be slightly weaker, but less side effect prone than chloroquine 19.

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 ophthalmologic. Prolonged therapy has been associated with fundal defects with maculopathy, especially peripheral vision and reduced night vision. Therefore regular ophthalmologic 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 24.
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 26,27.

4. Arava / Leflunomide

Arava is a drug that works in a similar fashion to methotrexate and is similar in both response, and potential side effect. It inhibits the inflammatory cascade. It has similar precautions, especially against use in pregnancy, or for several months before planning on pregnancy. It also has some problems associated with liver toxicity and requires monitoring. The drug however is effective with response over 3-4 weeks, and has been shown to reduce erosions of the bone and joints. It reduces structural deterioration. This is therefore a major advantage in management of RA. Dose requires a loading dose of 100mg daily for 3 days and then a maintenance of 20mg per day.

Monitoring requires at minimum baseline FBC, AST, ALT, GGT and pregnancy testing as required. The bloods should be repeated at 1 month then two monthly. Overdose or side effect may be treated using cholestyramine.

Main side effects include
Nausea
Rash
Alopecia
Hepatic enzyme elevation / hepatitis
Anaemia, leukopenia, Thrombocytopenia

5.. Sodium aurothiomalate / auranofin  - NOW ESSENTIALLY OBSOLETE

Gold has been shown to improve symptoms and signs of Rheumatoid arthritis, but toxicity is common, especially with injectable form 19,28.

Injectable gold is given in increasing doses over several weeks. Doses are started with a test dose of 25 mg, followed by 50 mg per week to a total of 1g or 6 months therapy. Thereafter a maintenance dose of 50 mg is continued 2 - 4 weekly. Response may take between 3 - 6 months to occur. Monitoring of injectable gold therapy requires blood count and urinalysis weekly prior to each injection for the first month, then 4 weekly.

Main side effects include:

  • Allergies with rashes
  • Diarrhoea
  • Conjunctivitis
  • Nephrotoxicity - especially proteinuria
  • Marrow suppression - especially thrombocytopenia.

Auranofin is used in mild disease, and has a high incidence of side effects including diarrhea nausea and skin rashes. The more serious side effects on the marrow and kidney are uncommon.

In the case of a rash - discontinue the drug, and allow the rash to settle. However rechallenge with the drug is often not associated with recurrence of the rash.

Pregnancy: There is little available data, with fewer than 100 cases of pregnancies on gold therapy. However there are no reported cases of teratogenicity. It is considered advisable to start the gold injections on the day of menses, to minimize risk of pregnancies on the drug 26. The drug must be stopped if pregnant.

6. D-Penicillamine.- NOW ESSENTIALLY OBSOLETE

D-Penicillamine is also shown in trials to be effective in rheumatoid arthritis 19,28,29. Response takes 3-6 months to see. Approximately 60 percent respond, but there is no effect on radiological progression and toxicity profile is significant.

Main side effects include:

  • Allergies with rashes.
  • Stomatitis.
  • Metallic taste.
  • Skin rashes - pemphigus, urticaria.
  • Drug induced lupus.
  • Myasthenia gravis.
  • Polymyositis.
  • Thyroiditis.
  • Goodpastures syndrome.
  • Diarrhoea.
  • Nephrotoxicity - especially haematuria and proteinuria.
  • Marrow suppression - especially thrombocytopenia.

Doses recommended include starting at 150 mg for 3 months and if no response, increasing by 150 mg every 4 - 8 weeks to a maximal dose of 750 mg per day if no response. Do not use concurrently with meals and in particular, not with iron or antacid preparations. It is generally recommended to take it in the evening.

Monitoring of D-Penicillamine therapy requires blood count and urinalysis two weekly for the first month, then 4 weekly.

Pregnancy: Data in pregnancy is limited. Teratogenicity is not confirmed but the drug should ideally be stopped 1 month before the planning of any pregnancy.

7.. 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. Use of the drug has been based on the theory that the disease may have an infective aetiology. Trials have been contradictory 30, but the balance of early trials showed benefit 31,32. Response included clinical as well as improvement in acute phase response. The MIRA study group (Minocycline in rheumatoid arthritis) showed an improvement in moderate severity RA, with modest, but significant benefit in RA. O'Dell has published recent data on the early use of minocycline in Rheumatoid arthritis, and reported a greater remission rate in patients treated early within the first year with minocycline 33. Radiological progression has not been slowed by use of the drug 34

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.

8. Cyclosporine

Cyclosporine is considered a more toxic drug and has largely been used with combination therapy with methotrexate. It as major side effect problems include hypertension and renal toxicity. It requires careful monitoring of the drug level. But cyclosporine is limited by cost factors that make it impractical for general use. It's only role in this country would be that of patients with drug resistance and in severe intractable disease.

9.. Azathioprine

Azathioprine (AZA) is a purine antagonist and is used in resistant disease.

Dose: 1.5-3 mg/kg/day

Side effects include:

  • Bone marrow suppression.
  • Infections.
  • Gastrointestinal intolerance.
  • Hypersensitivity hepatitis with cholestasis.
  • Malignancy risks: The risk of malignancy is not reported at doses used in the treatment of the rheumatic diseases, although it is reported in transplant patients treated with AZA.

Side effects require drug withdrawal, and are usually reversible.

Reproductive failure is not a problem with AZA.

Pregnancy : Teratogenicity is not seen, although use in pregnancy remains undesirable.

Monitoring: A full blood count is recommended 1-2 weekly initially and then monthly once disease stable.
Liver functions especially AST & ALT & GGT should be done 6 monthly.

10. Combination therapy

It is being suggested by several centers that combination therapy is the best form of therapy with better response rates compared to individual therapy. Combinations have been used in different formats, including "step-down models", starting with several drugs and then dropping agents consecutively, eventually maintaining a mild DMARD long-term 35. "Saw-tooth" models are also proposed. These entail early use of DMARD, with replacement of each in turn by another as the efficacy of the respective drug subsides 36. The standard practice with RA management however, remains initial treatment with single drug therapy. If patients do not show an adequate response, then the drug may either be substituted or a second DMARD drug added. A number of combinations have been shown to be potentially superior to monotherapy with respect to both efficacy and toxicity. These should de done under Rheumatologist supervision, especially in cases of resistance to monotherapy.

Regimen's include:

  • Methotrexate - Chloroquine
  • Methotrexate - Sulphasalazine
  • Methotrexate - Cyclosporine
  • Sulphasalazine - Hydroxychloroquine

O'Dell recommends continuation of triple therapy with methotrexate, sulphasalazine and hydroxychloroquine, thereby increasing remissions and reducing / preventing recurrence of disease 37. Initiation of combination therapy as the initial therapy may be indicated in severe disease but long term data is still required.

Recommendations for primary care practitioners:

1. Confirm the diagnosis as early as possible.
2. Assess degree of activity
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.

11. Anti- TNF therapy - Infliximab and Etanercept.

The use of biological agents is increasing with tumor necrosis factor receptor antagonist - Remicaide/Infliximab, being the first to register for use in RA, and now Spondyloarthropathies, and juvenile arthritis also being treated. The Medication is given as a infusion, dose determined by weight and given at baseline, 2 weeks , 6 weeks then 2 monthly. It is used with methotrexate to prevent antibody production to the drug itself (which is a chimeric antibody - part mouse, part human). The drug response is dramatic with reduction in inflammatory markers and reduction in swollen and tender joint counts. The drug however requires ongoing use and withdrawal results in the resurgence of disease.

Enbrel / Etanercept is a fusion protein of Tumour necrosis factor soluble i.e. circulating receptor. It is given as a subcutaneous injection twice a week at 25mg per injection for a normal adult. It has similar profile to infliximab, but is a pure human form and not susceptible to the antibody response to itself. It can be given with or without methotrexate.

Both drugs are used in resistant therapy rather than ab-initio. This is related to price constraints and also side effect potential. Major side effects are infection risk, and infliximab has been found to reduce defenses against tuberculosis, hence making use in Africa more difficult.

Other biological therapies include

Adalimumab an anti TNF human antibody 
Anti IL1 -  Kineret now available in USA

Ticilizumab - anti IL6
Rituximab - Bcell antagonist anti CD20 antibody
Abatacept Orencia - Co-stimulatory antibody

...and many more in pipeline development.

My recommendation for DMARD use

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References

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  38. The arthritis pages of drdoc on-line :
    http://www.arthritis.co.za


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This article is Copyright

Dr David Gotlieb
drdoc on-line
Cape Town
Oct 1999
Revised 2010