Changing concepts in the treatment of rheumatoid arthritis: be more aggressive

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1 MODERN MEDICINE Changing concepts in the treatment of rheumatoid arthritis: be more aggressive JOSEPH GOLBUS, MD Many experts advocate that the traditional pyramid approach to the treatment of rheumatoid arthritis be discarded in favour of more aggressive schemes. The new concept calls for combinations of potent drugs that are used earlier in the disease to suppress inflammation before bony erosions develop- It is hypothesized that the simultaneous use of multiple drugs not only overcomes cellular resistance to the medications, but reduces toxicity as well. ^ It is becoming increasingly clear that the so-called pyramid approach to treating rheumatoid arthritis is a failed concept. Patients who are treated in this manner often have suboptimal outcomes in terms of functional status and mortality. Rheumatologists now favour a much more aggressive approach to treatment. While some would call this new approach controversial, I do not. It is discussed at all our national meetings and in journal articles and is followed in daily practice. We clearly need to intervene earlier in the course of the disease and with more potent drugs. I do not, however, recommend a specific combination of drugs for all Dr Golbus is head, division of rheumatology, Evanston Hospital and assistant professor of medicine, Northwestern University Medical School, Chicago, USA. He wrote this article specially for MODERN MEDICINE. cases because we do not yet know which drug or combination is most effective. It has become common clinical practice to use several drugs simultaneously. This is similar to how oncologists utilize chemotherapy; most regimens they use are unproven and highly experimental, yet given the severity of the disease and the lack of acceptable, proven alternatives, combinations are being used. Traditional strategies For many years, we managed RA according to the traditional pyramid concept of sequential therapy (Figure 1). This approach involves the orderly progression of therapies, beginning with simple interventions and progressing over months or years to more potent medications. Typically, our treatment would begin with physical therapy and either a salicylate or a nonsteroidal antiinflammatory agent. Progression of the disease would prompt the addition of a corticosteroid or a single "diseasemodifying antirheumatic drug" (DMARD) such as gold, hydroxychloroquine, or penicillamine. If necessary, this would be followed by a cytotoxic agent such as azathioprine, methotrexate, or cyclophosphamide. This therapeutic progression could be stopped at any time if a good response was obtained. Although the pyramid regimen does seem to relieve pain and inflammation in the short term, it does not appear to significantly alter the longterm outcome in terms of functional status and mortality. 1 Further contributing to the inadequacy of this approach was the common practice of withholding the more toxic but potentially more effective therapies until after joint damage and disability had already occurred. The new strategies Based on the shortcomings of the traditional therapies and our new understanding of RA's DECEMBER 1992 / MODERN MEDICINE OF SOUTH AFRICA 19

2 continued. These new strategies call for using the more potent agents much earlier in the course of the disease. Cross section of the internal and external appearance of the knee in RA The main therapeutic goals are to relieve the patient's symptoms, prevent joint destruction, and maintain joint funct true morbidity and mortality, many experts advocate that we discard the pyramid approach in favour of a much more aggressive approach that is designed to totally suppress inflammation before irreversible bony erosions develop. 2 " 4 In one form or another, the new treatment strategies all call for "inverting the pyramid" that is, using the more potent agents much earlier in the course ofthe disease. Healey and Wilske, forexample,suggesta"step-down bridge," whereby numerous DMARDs and cytotoxic drugs are used very early in the disease in 20 MODERN MEDICINE OF SOUTH AFRICA / DECEMBER 1992 Illustration for MODERN MEDICINE by Diane Ne an attempt to induce remission. As the disease becomes better controlled, the more toxic drugs are dropped; remission is maintained with the safer agents. 2 This approach parallels cancer chemotherapy in that combinations of drugs are being

3 Some rheumatologists are using the traditional DMARDs in combination with cytotoxic drugs. The traditional prescribing strategy requires earlier intervention with the more potent drugs. General principles Surgery Combination therapies Intra-articular steroids Figure 1, The traditional pyramid approach involves the orderly progression of therapies, beginning with simple interventions and progressing over months or years to more potent drugs. This approach, which has been found wanting, is being replaced by a more aggressive course of therapy. utilized simultaneously in an effort to overcome celullar resistance to drugs and at the same time reduce toxicity. It is hoped that this modification of the classic pyramid approach will ultimately improve functional outcome and survival rates. Although we do not yet know which combinations offer the greatest benefit and the best toxicity profile, some rheumatologists are using the traditional DMARDs in combination with cytotoxic agents. Methotrexate has achieved considerable popularity in the last decade as a treatment option. Compared with the other DMARDs and cytotoxic drugs, methotrexate appears to have superior efficacy and safety and a quicker onset of action. 5 6 For these reasons, many rheumatologists use it early in the course of the disease and often in combination with other remittive agents. On a balancing, cautionary note, it is worth mentioning that not all RA patients have disease severe enough to justify the aggressive treatment schemes outlined in this article. For example, some of your patients can be well-managed with a nonsteroidal anti-inflammatoiy drug and a judicious balance of rest and exercise. Accordingly, it is important that we not only devise better treatment strategies, but also identify improved predictors of erosive disease. This prognostic information can help us better decide which of our patients Our main goals are to relieve symptoms, prevent joint destruction, maintain joint function, and, most important, preserve quality of life. We attain these goals through a variety of interventions. Extensive patient education, early occupational and physical therapy, and the use of anti-inflammatory agents make up the early steps of most treatment programmes: Education. Given the longterm physical, emotional, and economic consequences of the disease, patient education is essential. Make sure your patient understands the prognosis and has realistic expectations of therapy. This will lead to an improved outcome with less frustration and long-term disillusionment. A good education should provide the patient with basic information about the disease and reinforce the importance of compliance with all aspects of the treatment plan. Support. Try to involve your patient's family. Their emotional support can be very beneficial. Rest/exercise. A balanced programme of rest and exercise is a key component of the treatment plan. There is good evidence that rest may diminish the signs and symptoms of synovitis. And while it might seem to be contradictory, at the same time a regimen of exercise DECEMBER 1992 / MODERN MEDICINE OF SOUTH AFRICA 21

4 continued. The newer NSAIDs have a better therapeutic profile than plain aspirin, and patient compliance is generally good. The long-term outlook is worse than we thought Rheumatoid arthritis is an autoimmune inflammatory disease of unknown aetiology. Although it usually manifests during the third to fifth decades of life, it can affect all age groups. RA afflicts approximately 1 to 2% of the adult population worldwide. Its prevalence increases with age, and it affects twice as many women as men. By the age of 55, nearly 5% of women and 2% of men have the disease. Recent data have demonstrated that the long-term outlook for patients who have RA is far worse than previously believed, 2021 In addition to the high incidence of disability, it has become clear that RA accelerates mortality as well, particularly in those who have more advanced disease and extra-articular features. ' 22 Data from Pincus and Callahan have shown that patients who have functional class 3 or 4 RA have 10-year survival rates that are comparable to those of patients with Hodgkin's disease, diabetes mellitus, stroke, and threevessel coronary artery disease all of which are considered more "serious" than RA. 20 " 22 Joseph Golbus, MD and physical therapy is also vital. Physical therapists can provide an appropriate exercise programme aimed at maintaining or increasing joint motion, muscle strength, and, ultimately, joint function. Exercise can also promote an improved sense of well being. Finally, there are assistive devices and splints available that can greatly enhance your patient's comfort and improve functional status within the limits of pre-existing deformities. Surgery. In patients whose erosive disease has led to damaged joints and disability, surgery can often restore or improve some function. Those procedures that are often successful in RA patients include total hip and knee arthroplasties as well as several procedures for the hands and feet. When these interventions are used in combination with rational drug treatment and aggressive physical and occupational therapy, they can dramatically improve functional status and quality of life. Nonsteroidals/steroids Two long-standing treatments for RA are the nonsteroidal antiinflammatory agents and corticosteroids: NSAIDs. For many years, the mainstay of early therapy has been the nonsteroidal antiinflammatory drugs. The newer NSAIDs have a better therapeutic profile than plain aspirin with respect to major gastrointestinal toxicity. Moreover, patient compliance is generally better because of the more convenient dosing schedules. 24 MODERN MEDICINE OF SOUTH AFRICA / DECEMBER 1992 On the other hand, NSAIDs are more likely than aspirin to cause certain side effects hypertension, congestive heart failure, oedema, and renal insufficiency. These risks are of special concern in the elderly, who may already have some impairment of renal and/or cardiac function. As with all medications, the importance of monitoring for drug toxicity cannot be understated. The American College of Rheumatology recommends that every patient who starts NSAID therapy obtain a baseline blood count, blood urea nitrogen, creatinine, liver enzymes, potassium, and a urinalysis. These initial studies should be repeated in 1 to 3 months and then at 3- to 12-month intervals thereafter, depending on the patient's risk factors for NSAID toxicity. Corticosteroids. The proper role of corticosteroids in the treatment of RA remains controversial. According to the classic pyramid approach, low-dose steroid therapy has been used as a bridge to control inflammation that is resistant to NSAIDs until the DMARD exerts its effects. In recent years, as the risks of NSAIDs have become more apparent, many rheumatologists have come to favour the early use of low doses of prednisone (Meticorten et al), 5 to 7,5 rag/ day, in place of NSAIDs, especially in the elderly. Low-dose steroids have a favourable side-effect profile, and they can be effective in controlling inflammation in those patients

5 continued I The proper role of I corticosteroids in RA I remains controversial. who are at a high risk for NSAID-induced toxicities. In addition to oral corticosteroids, many RA patients benefit from a steroid injection into a particularly painful joint. The side effects usually associated with oral steroids are rarely encountered after intra-articular injections. DMARDs Among the disease-modifying antirheumatic drugs are gold, hydroxychloroquine, sulphasalazine, and D-penicillamine: Gold. Parenteral gold salts have been used to treat RA for more than 60 years. Although a recent report 8 has called into question their effectiveness, most experienced clinicians believe that gold salts can improve the symptoms and possibly delay or prevent the progression of bony erosions. A number of gold compounds are available for treating RA, including an intramuscular preparation, gold sodium thiomalate (Myocrisin). Auranofin (Ridaura), an oral absorbable gold preparation, was approved in the 1980s. While this compound is more convenient and less toxic than the parenteral gold salts, it is not quite as effective. Adverse reactions to gold are fairly common, the most frequent being skin rash, mucositis, proteinuria, and thrombocytopenia or leucopenia. Rare toxicities include colitis and pneumonitis. In general, adverse effects occur more often with the parenteral forms. (One exception: diarrhoea, which occurs in up to 50% of those who take oral gold. 9 ) Gold thiomalate may cause a nitritoid reaction, which is characterized by sweating, dizziness, weakness, nausea, and occasionally hypotension. Gold toxicity usually resolves with a temporary discontinuation ofthe drug. In patients who have milder rashes or proteinuria, therapy can often be reinstituted at lower doses. To properly monitor for toxicity, you should obtain a complete blood count, platelet count, and urinalysis before every gold injection; patients who take oral gold should have these studies performed once a month. Hydroxychloroquine. Antimalarials have been used to treat RA since the 1950s. Hydroxychloroquine sulphate is the most widely used because of its lower toxicity and equivalent efficacy compared with other drugs in this class. Although hydroxychloroquine has been shown to benefit some patients, relatively few achieve adequate long-term symptom control. For this reason, it is generally employed only in early disease (ie, no or minimal erosions on X-ray) for patients whose symptoms are refractory to NSAIDs alone. In view of its safety profile and its excellent record of patient acceptance, hydroxychloroquine is often added to other DMARDs to improve the therapeutic response. Furthermore, there is preliminary evidence that hydroxychloroquine may 26 MODERN MEDICINE OF SOUTH AFRICA / DECEMBER 1992 reduce the incidence of hepatic toxicity in patients who take salicylates or methotrexate. 10 I usually prescribe hydroxychloroquine at 200 to 400 mg/day. It may require 3 to 6 months of treatment before you will see any therapeutic effect. Hydroxychloroquine is extremely well tolerated. Only occasionally must a patient discontinue therapy because of a rash or GI intolerance. Corneal deposits may cause an episode of blurred vision, but this will resolve with a discontinuation of the drug. The most serious potential adverse effect is retinal toxicity, manifested by visual-field defects, central scotomata, and, ultimately, some vision loss. Fortunately, this complication is exceedingly rare at doses of 400 mg/day or less. 11 Because presymptomatic macular pigmentation can be detected during ophthalmological screening examinations, it is mandatory that all patients have thorough eye examinations at baseline and at 4- to 6-month intervals thereafter for the duration of therapy. S u 1 p h a s a 1 a z i n e. Sulphasalazine (Salazopyrin) was designed in the 1940s specifically for the treatment of RA. The proposed infectious aetiology of RA and its obvious inflammatory nature provided the rationale for combining a sulpha drug (sulphapyridine) with a salicylate (5-aminosalicylic acid). A number of controlled trials have demonstrated

6 With hydroxychloroquine, it may require 3 to 6 months before you see any therapeutic effect. But the agent is extremely well tolerated. sulphasalazine's efficacy in a percentage of patients with RA (although there may be more therapeutic failures with this drug than with other secondline agents). 12 The usual starting dosage is 0,5 grams twice a day, which you can increase by 0,5 grams weekly until you reach a maintenance dose of 2,0 to 3,0 grams/day taken in two or three divided doses. Sulphapyridine appears to be the active moiety in RA, as serum salicylate levels are usually very low. 13 Common adverse effects include GI intolerance, rash, dizziness, and headache. These symptoms necessitate treatment withdrawal in onethird of patients. Patients must be monitored with periodic complete blood counts because of the rare occurrence of neutropenia. D-penicillamine. The use of D-penicillamine (Penicillamine, Metalcaptase) has declined in recent years, mainly because methotrexate has emerged as a more effective and less toxic alternative. It is usually reserved today for patients in whom the other DMARDs have either caused toxicity or failed to control the disease. A "go low, go slow" approach to D-penicillamine therapy is essential to minimize the substantial risks of toxicity. 14 The recommended initial dosage is 250 mg/day taken with meals, with subsequent increases of 125 to 250 mg every 2 or 3 months, up to a maximum of1000 mg/day. Careful clinical and laboratory monitoring is mandatory; the blood count, platelet count, and urinalysis must be checked monthly. Penicillamine's toxicity profile skin rash, stomatitis, proteinuria, and cytopenia is very similar to gold's. Moreover, the drug may cause a severe taste disturbance (dysgeusia) and on rare occasions severe autoimmune syndromes such as pemphigus, polymyositis, Goodpasture's syndrome, myasthenia gravis, and bronchiolitis obliterans. Cytotoxic agents The three cytotoxic agents used for RA are methotrexate, azathioprine, and cyclophosphamide: Methotrexate. Although methotrexate wasfirstshown to be beneficial in the early 1950s, only in the last decade has it been widely prescribed. During this period, many controlled prospective trials and extensive clinical experience have convincingly demonstrated that methotrexate is a drug of superior efficacy and safety when compared with other DMARDs and cytotoxic agents. 15 The standard dosage of methotrexate ranges from 5 to 15 mg/wk. It is usually started as a single dose of 5,0 to 7,5 mg orally once per week or divided into two doses taken every 12 hours. The dosage is increased every 4 to 6 weeks as the clinical situation dictates. For patients in whom the oral form is not tolerated, or for those who are noncompliant, methotrexate can be given parenterally in doses of 10 to 25 mg once per week. One distinct advantage that methotrexate has over all other DMARDs and cytotoxic agents is its more rapid onset of action. Initial subjective improvement may occur as early as 3 to 4 weeks into therapy, with objective improvement in the synovitis often apparent in 6 to 8 weeks. Methotrexate, by inhibiting dihydrofolate reductase, interferes with the biosynthesis of purines and pyrimidines and, ultimately, DNA and RNA formation, resulting in cell death. Most of the drug is bound to serum proteins and slowly dissipates in cells and thirdspace fluids. For this reason methotrexate must be used with caution in patients with ascites or large pleural effusions. Because methotrexate is excreted by the kidney, dosage adjustments must be made for patients with impaired renal function, or the drug should be avoided altogether. The most common toxicities of low-dose weekly methotrexate involve the GI tract. Nausea, vomiting, diarrhoea, anorexia, and stomatitis are seen most often. In general, these effects are dose-dependent and most apparent in the first 24 to 48 hours after the patient takes the drug. Lowering the dose or lengthening the interval usually alleviates the problem. Hepatotoxicity from methotrexate has been a great concern. A substantial percentage of individuals on DECEMBER 1992 / MODERN MEDICINE OF SOUTH AFRICA 27

7 continued I One distinct advantage that I methotrexate has over all other I DMARDs and cytotoxic agents I is its more rapid onset of action, methotrexate will develop a chemical hepatitis with increases in the liver enzymes SGPT (alanine aminotransferase), SGOT (aspartate aminotransferase), and lactate dehydrogenase. Elevation of these enzymes above two and one-half times the upper limit of normal is an indication to withhold the drug temporarily. Once the enzyme levels have returned to normal, the drug can be restarted at a lower dose. Fortunately, cases of severe liver damage as a toxicity of methotrexate therapy are rare. Current practice is to check the liver enzymes initially at 2- week intervals, and then at 4- to 8-week intervals thereafter. Most rheumatologists believe that routine liver biopsies are not necessary. Risk factors for toxicity include alcohol use, diabetes, obesity, and older age. Low-dose methotrexate has been associated with two forms of pulmonary toxicity: a diffuse alveolar fibrosis and a more acute hypersensitivity pneumonitis. The clinical course of the latter condition may be fulminant with a rapid onset of fever, nonproductive cough, and dyspnoea. In addition to stopping the drug, high-dose corticosteroids are often given to suppress the inflammatory response. Because methotrexate pneumonitis produces a clinical course indistinguishable from infection, bronchoalveolar lavage, and/or biopsy are often required to establish the correct diagnosis. Severely ill patients should receive broad-spectrum antibiotics along with corticosteroids during the evaluation. Methotrexate is teratogenic and should not be used in pregnancy. Given that many individuals with RA are women in their child-bearing years, this warrants close attention. In men, methotrexate may cause oligospermia, although sperm counts return to normal after cessation of the drug. There is no evidence that methotrexate is carcinogenic at either low or high doses. Frequently used drugs that may raise the risk of methotrexate toxicity include the NSAIDs, barbiturates, oral contraceptives, and probenecid (Benemid et al). Azathioprine. Azathioprine (Imuran) is a cell cycle-specific antimetabolite. It undergoes rapid hepatic metabolism to 6- mercaptopurine and then further to a false purine analogue, thiouric acid. In doing so, it acts as a purine antagonist. Although its exact mechanism of action is unknown, azathioprine has been shown to act as an immunosuppressant. 30 MODERN MEDICINE OF SOUTH AFRICA / DECEMBER 1992 Several well-conducted controlled clinical trials have shown that azathioprine is effective in the treatment of RA; it is comparable to gold compounds, chloroquine, and penicillamine In general, we prescribe doses of 1,0 to 2,5 mg/ kg/day, starting with the lower doses and increasing them gradually. Like the other DMARDs, azathioprine has a gradual onset of action; it takes 4 to 6 months to achieve maximum benefit. Azathioprine is generally well-tolerated. Its major side effects, in order of decreasing frequency, are GI disturbances (abdominal cramping, nausea, vomiting, and diarrhoea being the most common), a mild, reversible leucopenia, and elevation of liver enzymes. Two forms of a rare hypersensitivity reaction have been described: an acute allergic hepatitis and a systemic illness with fever, rash, polyarthritis, and sometimes meningismus. Although there is a risk of malignancy with long-term use in renal transplant recipients, the risk of cancer is less clear. Many clinicians feel the risk of azathioprine-induced cancer in RA patients is minimal, or absent. But because of this potential risk, some doctors prefer to use the drug only in the elderly or in those in whom other remittive agents have failed. Cyclophosphamide. Cyclophosphamide is an alkylating agent of the nitrogen mustard group. It acts by covalently binding to DNA and RNA strands, thus inhibiting replication and cell division. Many controlled and uncontrolled trials have demonstrated that cyclophosphamide is extremely efficacious in suppressing synovitis and retarding bony erosions. 18 However, because of its toxicity (particularly the risk of cancer), its use is restricted to two very small subsets of patients: 1) those who have severe, advanced disease that does not respond to the other remittive agents and 2) those

8 continued. I Azathioprine is effective; it is I comparable to gold compounds, I chloroquine, and penicillamine. who have life-threatening extra-articular features of RA, such as rheumatoid vasculitis. Cyclophosphamide's shortterm toxicities include GI intolerance, bone marrow suppression (most often leucopenia), hair loss, and haemorrhagic cystitis. Its longterm use is limited by a potential for bladder fibrosis and carcinoma, serious infections, irreversible sterility, and haematological malignancies. Patients who receive cyclophosphamide for severe RA should undergo complete blood counts and urinalyses every month. They should also be encouraged to drink large volumes of fluid to ensure frequent emptying of the bladder. Combination therapy As noted earlier, the rationale for using combinations of DMARDs and cytotoxic agents is that you might achieve greater efficacy, especially if those drugs have different sites of action. In addition, the use of combinations of drugs in lower doses may diminish toxicities. Unfortunately, our knowledge of the mechanisms of drug actions and interactions is incomplete. We do not yet know which combination or combinations is most efficacious or the least toxic. Clearly, prospective clinical trials are needed to address the issue. Because of methotrexate's superior efficacy, safety, and quicker onset of action (compared with other DMARDs and cytotoxic drugs), many rheumatologists use it in combination with other remittive agents or cytotoxic agents. For reasons of safety, hydroxychloroquine is also frequently used in combination protocols. For an excellent discussion of the published trials of combination therapies in RA, I recommend the recent review by Wilke and Clough. 19 Conclusion In general, it would be wise to consult a rheumatologist when you are contemplating using DMARDs and/or cytotoxic agents. Before you use the more potent agents and use them earlier in the course of therapy, you want to be sure that the diagnosis is correct, that the patient has sufficient disease to justify the use of a more aggressive approach, and that there are no contraindications to therapy. 32 MODERN MEDICINE OF SOUTH AFRICA / DECEMBER 1992 rheumatoid arthritis: Update after a mean of 53 months. Arthritis Rheum, 1988;31: Brooks PM, Day RO. Nonsteroidal anti-inflammatory agents: Differences and similarities. N Engl J Med, 1991;324: Epstein WV, Henke CJ, Yelin EH, Katz PP. Effectofparenterally administered gold therapy on the course of adult rheumatoid arthritis. Ann Intern Med, 1991;114: Rocha MP, Burrichter PJ, Blodgett RC. Effect of chrysotherapy on the lower gastrointestinal tract: A review. Sem in Arthritis Rheum, 1987;16: Fries JF, Singh G. Lenert L, Furst DE. Aspirin hydroxychloroquine, and hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis. 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