Drugs 10: 394-425 (1975)

Antirheumatic Drugs: Clinical Pharmacological and Therapeutic Aspects C.J. Smyth andJ.F. Bravo University of Colorado Medical Center , Arthritis Division, Denver, Colorado

Table of Contents Summary 1. Current Concepts in the Pathogenesis of Rheumatic Disease 1.1 Immunological Factors 1.2 Infectious Agents 1.3 Hereditary Factors 1.4 Trauma .. . . . . . .. . . . . ... . . . . . . . . . . . . . .. .. .. .". . , . 1.5 Biochemical or Endo crine Factors . . 1.6 Proliferative Disorders 1.7 Allergic and Drug-Induced Arthritis 1.8 Neurogenic Factors 2. The Pharmacology of Join t Inflammation 2.1 The Kallikrein-Kinin-Kininase System 2.2 Drug Effects on Lysosomes 2.3 Drug Action and Prote in Binding . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Prostaglandins and Antirheumatic Drug Action .. . . . . . . 3. Pharmacokineric Properties of the Antirheumatic Drugs 4. Therapeutic use of Antirheumatic Drugs: The Principles and Aims of Drug Treatment 5. Treatment of Rheumatoid Arthritis 5.1 Treatment at Levell 5.1.1 General Basic Treatment 5.1.2 Salicylates 5.2 Treatment at Level 2 ; 5.2.1 Phenylbutazone and Oxyphenbutazone 5.2.2 Indomethacin 5.2.3 Phenylalkanoi c Acids Ibuprofen Calcium Fenoprofen Naproxen Ketoprofen Flurbiprofen

395 397 397 398 399 399 399 399 400 400 400 400 401 402 402 403 404 405 406 406 406 408 408 408 409 410 410 410 412 412

395

Antirheumatic Drugs 5.2.4 Other Drugs with Mild Anti-Inflammatory Activity Tolmetin . . . .. Alclofenac 5.2.5 Anthranilic Acids Flufenamic Acid Mefenamic Acid . Meclofenamic Acid 5.2.6 Antimalarials 5.2.7 Intra-Articular Corti costeroids 5.2.8 Non-Narcotic Analgesics Paracetamol . Dextropropoxyphene 5.2.9 Tranquillisers and Muscle Relaxants 5.3 Treatment at Level 3 . 5.3.1 Gold Salts . 5.3.2 Oral Corticosteroids . 5.3.3 Adrenocorticotrophic Hormone 5.4 Treatment at Level 4 . 5.4 .1 Hospitalisation . 5.5 Treatment at LevelS : Investigational Therapy 5.5.1 Cyclophosphamide . 5.5.2 Azathioprine 5.5.3 D-Penicillamine . 6. Juvenile Rheumatoid Arthritis 7. Ankylosing Spondylitis 8. Osteoarthrosis . . . . . . . .. 9. Polyrnyalgia Rheumatica 10. Adverse Reactions, Toxicity, Special Risk Patients

412 412 412 413

413 413

· . . . .. . . . .. · ·

413 413 414 414 414 414 415 415 415 416 417 418 418 418 418 419 419 420 421 421 422 422

Key Words' Anti-inflammatory agents There are many current concepts of the pathogenesis of rheumatic diseases which incor- Corticosteroids Cytotoxic agents porate immunological, infectious and hereditary D-Penicillamine factors. Rheumatic diseases may sometimes become apparent after trauma, be associated with Gold certain diseases and may be induced by nerve Indomethacin Non-steroid anti-inflammatory agents damage and serum sickness. Systemic lupus erythePhenylbutazone, oxyphenbutazone matosus may result from the use of a variety of Rheumatoid arthritis drugs. At present the body of evidence tends to incriminate immunological factors as well as infec- Salicylates tious agents as principal factors in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus . Just as there is uncertainty regarding the pathogenesis of rheumatic diseases, knowledge of the mechanism of action of the various drugs used to treat these diseases is also Summary

1 See subject index in each issue for further indexing terms .

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396

incomplete. Recent progress indicate s that inhibition of prostaglandin biosynthesis and possibly lysosomal membrane stabilisation are primar y modes of action of the anti-inflammatory agents. Certain antirheumatic drugs have also been shown to exert some of their therapeutic effect by interfering with the kallikrein-kinin-kininase system . In the management of rheumatoid arthritis, a 5-level pyramidal plan of therapy is described which offers a realistic approach to the treatment of patients in various stages of this disease. The general basic medical treatment consisting of rest, psychological adjustment, pain relief, measures to combat anaemia , exercise and a wen balanced diet and salicylate therapy, form the foundation of the pyramid. For many patients with low-grade disease and little disability, this level of therapy may give adequate control for long periods and no additional measures need be considered. In moderately severe disease affecting multiple joints with considerable constitutional disturbance and disability, when the basic medical treatment proves inadequate after several weeks of trial, additional measures are needed . These include the use of non-steroidal anti-inflammatory agents such as phenylbutazone, indomethacin and the phenylalkanoic acid derivatives, the antimalarials , and the anthranilic acid derivatives. Also included in this second level of therapy is the intra-articular administration of corticosteroids. Among the forms of drug treatment making up the third level of the pyramid are oral corticosteroid therapy and gold therapy. Of all the anti-inflammatory and long-acting agents commonly used in the treatment of rheumatoid arthritis, only gold salts may alter the clinical course or stop progression of the disease. Toxic reactions to gold are of the utmost importance, those involving the kidney or bone marrow being potentially the most serious. The corticosteroids are the most powerful anti-inflammatory compounds available, but their use in rheumatoid arthritis remains controversial. There is no convincing evidence that these drugs stop or significantly alter the natural course of the underl ying disease. None of the newer steroid derivatives have any advantages over prednisone or prednisolone, and their greater potency makes dosage adjustment difficult. Treatment at level four involves hospitalisation. There is growing recognition of the value of 4 to 6 weeks of intensive hospital care for rheumatoid arthritic patients who do not respond to the measures already mentioned. Treatment which is still investigational is involved at level five and includes the use of new orthopaedic procedures and devices and drugs under clinical investigation that have been shown to be promising. Such drugs include immunosuppressive and cytotoxic drugs such as azathioprine and cyclophosphamide, and D-penicillamine. Use of immunosuppressive drugs in rheumatoid arthritis should be restricted to patients in whom all forms of conventional treatment have failed to curb rapidly progressive disease with life-threatening complications. D-penicillamine has been used particularly in the treatment of severe rheumatoid arthritis with vasculitis. Its use is limited by side-effects, some of which are hazardous. In juvenile rheumatoid arthritis salicylates are still the treatment of choice. Gold therapy is the second best choice and is the only treatment that may influence favourably the course of the disease. Treatment of ankylosing spondylitis differs from that of rheumatoid arthritis in that gold therapy is ineffective. There is no medication which will alter the natural course of the disease, but indomethacin or phenylbutazone elicit symptomatic improvement. The main concern in osteoarthrosis is to relieve pain and analgesics such as aspirin or paracetamol are useful. As there is little or no inflammation in affected joints in this disease the role of anti-inflammatory drugs is limited . Polymyalgia rheumatica is best treated with oral corticosteroids, and other antiinflammatory agents are not indicated once corticosteroids have been started.

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397

1. Current Concepts in the Pathogenesis of Rheumatic Disease

The pathogenesis of connective tissue diseases (CTD) is not completely understood at the present time. In some of these disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) , the body of evidence tends to incriminate immunological factors as well as infectious agents.

1.1 Immunological Factors In SLE, immune complexes containing immunoglobulins (IgG and IgM)and complement occasional fibrinogen, are deposited in the basement membrane of the glomeruli, in the derrno-epidermal junction and also in vessels of the spleen, heart , lung and liver. These deposits can be demonstrated clearly by immunofluorescent techniques. Experimentally , similar findings can be reproduced in rabbits with the injection of foreign proteins such as bovine serum albumin (Christian , 1969). This experimental model plus the fact that serum of patients with SLE have a wide variety of auto-antibodies to tissue and nuclear antigens give strong support to the immunological pathogenic theory in SLE. Furthermore, DNA, anti-Dbla and other auto-antibodies can be demonstrated as forming part of the immune complexes deposited in the renal lesions. In RA, evidence in favour of immune process comprise the following (Zvaifler, 1970): 1) Lymphocyte infiltration of synovial membrane with atypical follicle formation. 2) Synthesis of rheumatoid factor (RF) of the IgM and IgG type in the synovial membrane by plasma cells. 3) Decreased complement in the synovial fluid. 4) Presence of IgM, IgG and complement components in the synovial membrane and other sites of tissue damage. S) Presence of antigen-antibody complexes , especially IgG-rheumatoid factor, in the synovial fluid. 6) Presence of these complexes, IgM (RF) and complement components in synovial fluid leucocytes , seen at cytoplasmic inclusions, which can be demonstrated with immunofluorescent techniques. The complement cascade is activated by these immune complexes producing leucotaxis, polymorphonuclear leucocytes arriving at the site and producing an inflammatory reaction due to the release of hydrolases from their lysosomal granules. The synovial membrane reacts producing IgG which is thought to stimulate RF production by plasma cells in the synovial membrane as well as in

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the regional lymph node. These lysosomal hydrolases seem to be responsible also for erosion of the articular cartilage in association with the advancing synovial pannus.

1.2 Infectious Agents Regarding the role of infectious agents in RA, there is no single organism which can be blamed with certainty. Many have been considered and discarded in the past. Mycoplasma, a pleuropneumonia-like organism (PPLO), is of interest since it has been associated with arthritis in cattle , chickens and mice (Sharp, 1970). A few reports of their presence in RA patients have appeared, but the possibility of contamination cannot be ruled out. Repeated attempts by competent investigators have failed to recover viruses from synovial fluid or tissues or to see them under the electron microscope. Interest in this promising area of research continues in many centres because of the association of arthritis in diseases such as rubella or infectious hepatitis. Viruses also have been implicated in an arthritic illness in minks known as Aleutian mink disease; arthritis also occurs in equine infectious anaemia in which there are connective tissue lesions and hypergammaglobulinaemia. The strongest evidence supporting the viral theory in the pathogenesis of any human CTD is in SLE. The spontaneous SLE picture occurring in the NZB/NZW mouse has glomerulonephritis and similar immunopathological fmdings to those of human SLE. Chronic viral infections have been demonstrated in these animals, but causal relationships have not been proven (Lambert and Dixon, 1968). Virus-like particles have been seen by electron microscopy in kidney and skin of patients with SLE but conclusive cultural evidence is lacking. The most attractive hypothesis of the pathogenesis of any of the CTDs is a combination of an infectious agent with the immunological factors acting together. A chronic viral infection could determine production of autoantibodies. On the other hand, it is possible that altered immunological mechanisms may facilitate chronic infection. A hidden virus of immunological abnormality would induce auto-antibodies which could then unite with the antigens and complement forming immune complexes which would produce damage by depositing in vessels and basement membrane of the glomeruli. Also, the activated complement sequence would attract neutrophils which, while phagocytosing these immune complexes, would release lysosomal cathepsins which would produce tissue damage. In Reiter's syndrome , infectious agents have been implicated. There is no doubt that the dysenteric form can be produced by Shigella dysenteriae, as is well documented in the ship outbreak reported by Noer (1966) . Whether an allergic response to the gonococcus or direct invasion of Bedsonia (a chlamydial

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399

organism belonging to the lymphogranuloma venereum tracoma group) [Schachter et al., 1966] are aetiologic factors still remains to be proven. 1.3 Hereditary Factors A familial tendency is noticed in CTD, and it is not rare to see relatives with the same disease or different types of collagen diseases, such as one with RA another with SLE or one with Raynaud's phenomenon. SLE has been reported in twins (Leonhardt, 1964) . The high frequency of one type of human lymphocyte antigen (HL-A W27) in ankylosing spondylitis and other axial arthropathies also points to hereditary factors . Some other rheumatic diseases that have a congenital or inherited basis are: Marfan's syndrome , homocystinuria, Ehlers-Danlos syndrome, mucopolysac charidoses and congenital dysplasia of the hip . The tendency for Heberden's nodes (osteoarthritis of the distal interphalangeal joints) to occur in women is well established . 1.4 Trauma It is well known that trauma may be responsible for degenerative arthritis in a single joint. In most cases, it is impossible to determine if trauma has an aetiological significance, or if injury is just co-incidental. Frequently, a traumatic episode will draw attention to a joint that is already the site of mild arthritis. At times, a direct blow may aggravate a pre-existing condition or it may activate a dormant arthritis. 1.5 Biochemical or Endocrine Factors The following diseases may be associated with arthritic changes, although the exact influence of these factors in the production of the joint change is unknown : hyperparathyroidism, hypo- and hyperthyroidism, haernochromatosis, ochronosis, Paget's disease, Wilson's disease, amyloidosis, agammaglobulinaemia, haemophilia, acromegaly, scurvy and hyperlipoproteinaernia type II. 1.6 Proliferative Disorders Systemic diseases such as leukaemia and multiple myeloma may also have associated arthritis. Primary neoplasms may affect the synovium (synovioma) . Metastasis may localise in joints. In dermatomyositis in adults over age 40, co-existence of malignant disease is found in 50%. Hypertrophic osteoarthropathy is a disease characterised by clubbing of the fingers and toes, pain and tenderness in the long bones

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400

(periostitis) and arthralgias or acute polyarthritis; in many cases, it is secondary to an underlying malignancy, frequently carcinoma of the lungs. 1.7 Allergic and Drug-Induced Arthritis The most classical example of an allergic arthritis is serum sickness. Druginduced SLE can result from the use of a variety of medicines, but the most frequent and most commonly recognised offenders are procainamide (Molina et al., 1969) and hydrallazine (Hahn et al., 1972). Others include isoniazid, aminosalicylic acid, certain anti-convulsants, barbiturates, penicillin, D-penicillamine, sulphonamides, tetracyclines, propylthiouracil and ex-methyldopa. 1.8 Neurogenic Factors Damage of the nerve supply to a joint plays a fundamental role in neurotrophic arthropathies. Recognised causes for these markedly destroyed joints are syphilis (lues), diabetes mellitus, syringomyelia, myelomeningocele, yaws and congenital insensitivity to pain. Other connective tissue diseases secondary to neurogenic factors are the shoulder-hand syndrome and entrapment syndromes.

2. The Pharmacology ofJoint Inflammation

Inflammation in connective tissue diseases is a complex process mediated by a variety of incompletely understood mechanisms, and it is far from clear how the antirheumatic drugs exert their effects. The known mediators include kinin peptides , lysosomal enzymes and prostaglandins, each resulting from a sequence of different events, but all resulting in vasodilatation , increased capillary permeability, oedema, pain and leucotaxis. Although our understanding of how anti-inflammatory drugs work is limited, recent intensive chemical and biological studies have contributed much regarding the mode of action of the various classes of these agents. A brief review of some of the opinions that have been advanced to explain the wide spectrum of actions of the commonly used anti-inflammatory drugs is given in the following sections. 2.1 The Kallikrein-Kinin-Kininase System The kinins are formed from plasma kininogen and can produce the cardinal signs of inflammation when this system is activated by a variety of stimuli (fig. 1) [Nies and Melman, 1968]. Certain antirheumatic drugs have been shown

Antirheumatic Drugs

40 1

to exert some of their therapeutic effect by interfering with the kinin system. The glucocortico ids act by blocking the conversion of inactive plasma kallikrein to active kallikrein by the Hageman factor, or this same precursor that is derived from glandular kallikrein or granulocytes. Aspirin is known to interfere with the formation of active kallikrein from both inactive plasma kallikrein and leukocyte s. This drug also will diminish kinin-evoked pain at the tissue level (note blocking sites in fig. I) .

2.2 Drug Effects on Lysosomes The relationship of the lysosomal enzymes to the production of tissue injury in the various connective tissue diseases has been clearly shown by the

Glandular kallikreins

Inactive plasma

f--

r---

kallikrein

[11

:=

Activated Hageman factor

r---

'" [1](2J

[I] [2]

-----

Granulocytes

Hageman factor

Active kallikrein

...

Plasma

kininogen (Q;zglobulin)

r

8

Kinins

[21* Smooth muscle constriction

Vasodilatation

Capillary

permeabl litv

Fig. 1. Diagrammatic presentation of the sites of anti-inflammatory action of glucocorticoids [1] and salicylates [2] with respect to the kallikrein-kinin-kininase system. Kinins are forme d from kininogen by the action of kallikrein which is foun d in plasma, various exocrine glands and granulocytes. Hageman factor is often necessary for kallikrein activation. Kallikrein activation is inhibited in some systems by several anti-inflammatory agents .

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studies of Weissmann(1972) , Ignarro (1971) and Chayen et a1. (1971). In joints, whether the initial insult is provided by micro-organisms, crystals or an antigenantibody complex, the final common pathway is the release of inflammatory lysosomal enzymes which leads to leucocyte infiltration, joint injury and cartilage destruction. Agents known to disrupt lysosomes will induce arthritis when injected into rabbit joints. On the other hand, those agents that have a lysosome-stabilising effect reduce inflammation. Among the antirheumatic agents that have been demonstrated to stabilise the membranes of the lysosomes are indomethacin, chloroquine, aspirin, phenylbutazone, oxyphenbutazone, flufenamic acid, mefenamic acid, glucocorticoids and gold. Gold salts are selectively taken up by lysosomes of macrophages. Phenylbutazone has not been shown to have any effect on lysosomal membranes directly, but it appears to exert this pharmacological effect , at least in part, by inhibiting the release of lysosomal enzymes into the circulation. Indomethacin, as one of its actions, inhibits the migration of leucocytes and thus prevents lysosomal products from these cells from reaching inflammatory sites.

2.3 Drug Action and Protein Binding There have been many attempts to correlate the clinical effectiveness of the anti-inflammatory drugs with the binding of drugs to plasma proteins. Hichens (1974) has recently extensively reviewed the protein binding of drugs and concludes that, 'the net result of this work so far is disappointing in terms of understanding why anti-inflammatory drugs have therapeutic value. If there exists a single most important site of action (receptor) for these drugs, then albumin binding sites are probably roughly analogous in general nature but considerably less demanding of precise configuration, and further work along these lines is unlikely to contribute anything more than bulk to the already voluminous literature'.

2.4 Prostaglandins and Antirheumatic Drug Action Evidence is accumulating that strongly supports the hypothesis that the inhibition of prostaglandin (pG) synthesis is an important mechanism for some of the actions of the corticosteroids and certain non-steroidal anti-inflammatory drugs. Vane (197 I) demonstrated that indomethacin, aspirin and salicylic acid inhibited the production of two prostaglandin enzymes (PGE 2 and PGF 2 a) ; Tomlinson et a1. (1972) showed that naproxen also inhibits prostaglandin

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403

synthesis in vitro. In concentrations likely to be found in body fluids during therapy the prostaglandins are potent vasodilators and are capable of inducing oedema, erythema and pain following intradermal injection. They have also been detected in man in the inflammatory exudates from blister fluid and in animals in experimental inflammatory states such as burns .in dogs and the familiar carrageen-induced paw oedema of mice (Hichens, 1974) . In man, with a skin window technique, PGE 1 and PGF 1 a did not alter the sequence and number of cells of the exudate of cutaneous inflammation. However, prostaglandins may be responsible for the accumulation of monocytes, one of the aspects of the conversion of an acute inflammatory reaction into a chronic one (Ferreira and Vane, 1974). It has also been shown that peritoneal macrophage migration from a capillary tube is inhibited by phenylbutazone (50mg/ml). This observation strongly suggests that this drug action is on monocytes , but such a direct action is not proven (Di Rosa et al., 1972). Another action of prostaglandins noted by Ferreira and Vane (1974) is that these substances in low concentrations sensitise pain receptors to stimulation by other inflammatory mediators (e.g. histamine and bradykinin) . In this way, they explain the analgesic action of aspirin-like drugs by the prevention of prostaglandin release which in turn , prevents sensitisation of the pain receptors to mechanical or chemical stimulation . In summary, it is evident that knowledge is incomplete regarding the mechanism of action of the anti-inflammatory drugs, but recent progress indicates that prostaglandin synthesis inhibition and possibly lysosomal membrane stabilisation are primary modes of action .

3. Pharmacokinetic Properties of the Antirheumatic Drugs

In this review no attempt will be made to bring together the vast knowledge that exists regarding the metabolism of the commonly used antirheumatic drugs. The pharmacokinetics of steroids used to treat inflammation have recently been reviewed by Fotherby and James (1972) . References to the extensive information on aspirin and related salicylates can be found in the reviews by Levy and Leonards (1966) and Davidson (1971) , and information on the chemistry and pharmacology of the non-steroidal anti-inflammatory drugs can be located in excellent reviews by Wiseman (1974) and Ober (1974) . Drug interactions involving anti-inflammatory compounds have been comprehensively reviewed by Sher (1971) [see also table II] . Some of the pharmacokinetic properties of the phenylalkanoic acid derivatives, commonly used in the treatment of rheumatoid arthritis are summarised in table I.

404

Antirheumatic Drugs

Table I. Some pharmacokinetic properties of the phenylalkanoic acid derivatives commonly used to treat rheumatoid arthritis Drug

Oral absorption

Effe ct Half-life of food' (hours)

Protein binding (%)

Biotransformation?

Ibuprofen Fenoprofen Naproxen Ketoprofen

readily ~ 8 0%

++ +

complete readily

Nil ?

99 > 99 99 .6 < 94

+ +++ ++

1.9 3 12-15 1.6 -1.9

?

Urinary recovery ' (%)

~67

> 90 > 95 < 90

I + = small influence ; ++ = considerable influence 2 + = slight ; ++ = moderate ; +++ = marked 3 Urinary recovery of unchanged and metabolised drug

4. Therapeutic Use of Antirheumatic Drugs: The Principles and Aims of Drug Treatment Unfortunately there is no aetiological cure for the great majority of arthritic patients. Because of this, the aim of therapy is to help the patient symptomatically. The benefits of treatment need wider recognition . There is great satisfaction both to the patient with chronic disabling arthritis and to the clinician to witness even minor improvement in the patient's condition. It may make the difference between depression or happiness. The main objectives of drug therapy are : 1) Relief of pain (analgesia) 2) Reduction or suppression of inflammation (anti-inflammatory effect) 3) Achievement of the above two objectives without undesirable sideeffects. Such problems are specifically encountered with anti-inflammatory medications. As a corollary of relief of pain and inflammation, another objective is the preservation of function of joints and muscles. Although outside the scope of this article, the tremendous importance of rest and appropriate exercises in the preservation of function as an adjunct to medical treatment, cannot be overemphasised. Furthermore, the function of corrective surgery has recently made major advances, and by selected procedures, the function of joints may be greatly improved. The gains following surgery are often far beyond benefits from medicines alone. The objectives of therapy as stated by Hollander (1974), i.e. 'the physician who has treated his patient for many years for a severe, chronic,

405

Antirheumatic Drugs

incurable arthritis can realise great satisfaction from seeing his patient still able to carry out his daily activities, minor deformities and continued mild pain notwithstanding' , deserve further emphasis.

5. Treatment ofRheumatoid A rthritis In order to develop a plan of management , the clinician must know his patient . He must take the time to learn the patient's fears, foibles and concerns, and to gain an insight into his or her intelligence and motivation and understanding of the disease. The patient's socio-economic status also needs consideratio n. Past and present treatment and response to it, including toxicities , are important. In the selection of drugs, it is imperative to know whether or not the patient has or has had peptic ulcer, gastro-intestinal bleeding, diabetes, hypertension, or renal, hepatic or haematopoietic disease. Another early consideration is the clinical course of the disease. The therapeutic problems will depend on the degree of activity, extent of structural

Stage I I monocyelie 35 % Normal

Stage II

Ai

::> 2 yrs. I Time

II polyeyel Ie 50%

Normal ~

i

Time

I I I I I

III pro gressive 15%

Stage III

St age IV

I I I I

I

•

~ . I I

I I

I I

Normal

;

Time

Basic progra mme

~

Analgesic drugs

> 0. E

~

.

Anti-inflammatory drugs

Rehabilitation

measures

PI I

Preventive

Splints, exercises, heat etc . Non-op erative orthopaedics

I

•

I Reconstructive

• Correct ive physical therapy : Operat ive orthopaedics

Fig. 2. The clinical course of rheumatoid arthritis in three hypothetical cases is represented in the upper half, the increases and decreases in disease activity being shown in the perpendicular and time along the horizontal. The lower part shows the relationship of therapy to clinical course and stage. What is done depends on when therapy is to be given.

Antirheumatic Drugs

406

and functional damage and rate of progression. These factors, together with any existing complications such as anaemia, pulmonary infiltrates, vasculitis, iritis, osteoporosis, etc. , are useful guidelines in planning therapy . Figure 2 is an aid to better understanding of the relationship of therapy to the disease. It combines the four stages of pathological classification as defined by the American Rheumatism Association (Ropes et al., 1958) and the three most common clinical courses of the disease. It may serve as a useful guide in planning therapy . Clearly the aims of a comprehensive programme in an early stage of the disease will emphasise relief of pain, suppression of inflammation, maintenance of function , prevention of deformities, education of the patient and his family and assistance in psychological adjustment. Later in the illness, most of these objectives will be the same, but in addition, rehabilitative measures will be used. In the later stages of the disease (III and IV), special efforts will be made toward restoring lost function . An overall therapeutic plan for the patient with rheumatoid arthritis can be constructed like the ancient pyramids. These were built on a broad and stable base; in a similar manner, the plan of therapy for rheumatoid arthritis presented here is founded on the so-called basic medical programme (fig. 3). All additional measures are added on top of this foundation. In this way, a step-wise pyramidal programme can be developed. The later measures to be used will depend upon the stage of the patient's arthritis and his or her response to the more basic measures indicated by the levels of therapy shown in the diagram.

5.1 Treatment at Levell (Base of the Pyramid)

5.1.1 General Basic Treatment There is general agreement about the value of rest, psychological adjustment , relief of pain, measures to combat anaemia, exercise and a well-balanced diet in all stages of rheumatoid arthritis. This basic programme is the foundation of the pyramid (fig. 3, level 1). These general measures are to be incorporated into the total plan of management for every patient with this disease. In many patients with mild and early disease, the improvement that occurs with basic medical treatment alone may be all that is necessary. For many patients with low-grade disease and little disability, this level of therapy may give adequate control for long periods and no additional measures need be considered.

5.1.2 Salicylates Aspirin is still the most widely used anti-inflammatory agent when given at high doses of over 4g a day. With these doses, serum salicylate levels of 20 to 30mg/ 100ml are usually achieved, which are considered by most clinicians to be

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the best therapeutic range. Smaller doses are less irrit ant to the gastro-intestinal tract but act mainly as an analgesic and have lesser anti-inflammatory effect. It is recommended that every newly diagnosed rheumatoid arthritis patient be started on aspirin unless it is contra-indicated (e.g. in cases of allergy, peptic ulcer , bleeding tendency , etc.). Maximum tolerable doses should be used. To accomplish this , the daily dose should be increased up to a dose producing tinnitus and then reduced 2 or 3 tablets below that level. However , this method may be unreliable in patients with pre-exist ing hearing loss (Morgan et al., 1973). Thus hearing , especially in elderly patients, should be assessed before relying on tinnitus as a means of determining optimum dosage of salicylates, If gastro-intestinal intolerance occurs , aspirin should be taken with milk, antacids or meals. However , ant acids cause more rapid excretion of the drug. Buffered aspirins are tolerated better. Enteric coated aspirins are useful, but sometimes not fully absorbed. Other salicylate preparations (sodium salicylate, calcium salicylate and choline salicylate) may be substituted for aspirin ; they all have significantly less gastro-intestinal to xicity but are not as efficacious . Benorylate is an ester of aspirin and paracetamol which has been shown to be an effective analgesic and ant i-inflammatory drug (Bain and Burt , 1970). The effects of 4g benorylate twice daily were indistinguishable from those of aspirin 1.2g 4 times daily (Beales et al. , 1972) . The advantage over aspirin alone is that it causes slightly less gastro-intestinal blood loss. The recommended dose is 4 to 8g a day in divided doses.

Level, of therapy

Invest igational therapy and

procedures

Rec o nst ructive

I 0..1

I

stero ids

Prev en tive surgery

N O ~'lt &roida l

Intra-

drugs

artic ular ster oids

anti·inflammatory

I EduCl tion PBtient family

society

I

surgery

I

Gold

Arth ritis

I

rehab ilitat ion

centre

I

Hospit alisat ion

N on narcot ic

Inte nsive

ph ysical

and occ upat ional

Or thopaedic

devices

Heat

Therapeutic exercise

Emo tio nal Joint

tranq uilliser relax ant.

I

Basic programme Rest

analgesic. lind

Salicyl, tet to tolerance

Nutr itio n

System

Fig. 3. Pyramidal plan of management of rheumatoid arthritis. The measures in levels 2 to 5 are added to the basic programme to meet specific therapeutic challenges.

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Salicylate hepatotoxicity has recently been described in patients with systemic lupus erythematosus (Seaman et al., 1974) and juvenile rheumatoid arthritis (Rich and Johnson, 1973). 5.2 Treatment at Level 2 In moderately severe disease affecting multiple joints with considerable constitutional disturbance and disability when the basic medical programme proves inadequate after several weeks of trial, additional measures are recommended. These include the use of anti-inflammatory drugs and antimalarials (fig. 3, level 2). 5.2.1 Phenylbutazone and Oxyphenbutazone These closely allied agents have both analgesic and anti-inflammatory properties, and in some rheumatoid arthritic patients, are more effective than salicylates. Given in a dosage of 100 to 300mg a day, they have been found to be well tolerated and of definite benefit in about 20% of patients with rheumatoid arthritis. Because of their potential capacity to produce toxic reactions including oedema due to sodium retention, skin rashes, activation of peptic ulcer with haemorrhage or perforation and bone marrow depression with agranulocytosis and thrombocytopenia (rarely at dosages of less than 400mg daily), their use must be supervised with care. A complete blood count should be done monthly for the first 3 months, then once every 3 months. A word of caution should be added concerning the use of these drugs with anticoagulants, as they may potentiate the anticoagulation effect of the coumarins by displacing them from plasma binding sites (table II). It should also be remembered that phenylbutazone competes for the same binding sites on human plasma albumin as do the sulphonamides and tolbutamide which could result in toxicity or increased therapeutic effect depending on the drug being displaced. 5.2.2 Indomethacin This drug has been in clinical use for more than 10 years and has aroused much interest and some controversy . Published reports on indomethacin give widely diverse opinions regarding its therapeutic effect in rheumatoid arthritis . Most of the reports that express a favourable opinion are written by practising rheumatologists and are based upon experience gained in treating large numbers of patients. Among these authors are many highly respected clinicians known for their honest and critical judgment. In 1965 our group (Smyth, 1965) concluded from a study of rheumatoid arthritic patients that indomethacin suppressed joint inflammation and improved function in approximately 25% of the patients. It may be necessary to use the drug for 2 to 4 months to attain maximum thera-

409

Antirheumatic Drugs Table II. Clinically significant anti-rheumatic drug interactions

Anti-rheumatic Drug

Patient receiving

Possible drug interaction

Aspirin (in high doses)

Corticosteroids Anticoagulant Sulphonylurea Methotrexate Probenecid and sulphinpyrazone

Non-therapeutic serum salicylate level Increased risk of bleeding Potentiates sulphonylurea Potentiation; pancytopenia Probenecid and sulphinpyrazone inhibited

Corticosteroid

Diuretics (thiazides) Barbiturates

Increased risk of hyperglycaemia Increased metabolic clearance rate of steroid

Phenylbutazone

Anticoagulant Sulphonylurea Bishydroxycoumarin (dicoumarol) Anticonvulsants (hydantoins)

Anticoagulant potentiation Potentiates sulphonylurea Potentiates anticoagulant

Probenecid

Indomethacin potentiated

Indomethacin

Potentiates anticonvulsant

peutic effect. After nine additional years experience, we still have the same opinion. The high frequency of untoward reactions to indomethacin is a major drawback. The most common undesirable effects are gastro-intestinal reactions, including nausea, epigastric distress or pain, vomiting and peptic ulceration . Next in order of frequency, are central nervous system symptoms. At least 25% of patients receiving the drug have headache and about 15% have vertigo and dizziness. Somnolence, stupor and hallucinations are rare. As the frequency of adverse reactions is related to dosage, it is recommended that the daily dosage be kept relatively low. At present, it is our policy to prescribe an initial dosage of 25mg at bedtime for one week and increase this by 25mg at weekly intervals until a maintenance level of 75 to lOOmg per day (in divided doses) is reached. When dosage is increased slowly according to this plan over the first 4 weeks, the great majority of patients will tolerate the drug and an effective therapeutic level can be attained. 5.2.3 Phenylalkanoic Acids This new group of compounds contains several non-steroidal anti-inflammatory drugs (Willkens and O'Brien, 1974) , such as ibuprofen, calcium fenoprofen ,

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flurbiprofen, naproxen and ketoprofen (fig. 4) . They are useful as analgesics with mild anti-inflammatory properties. Ibuprofen This anti-inflammatory drug has been extensively used in Europe and was recently approved by the Food and Drug Administration in the USA. At usual doses, ibuprofen has analgesic activity comparable with that of aspirin (Davies and Avery, 1971) in the treatment of rheumatoid arthritis, but at doses of up to 1,200mg has only slight anti-inflammatory activity . When it was introduced, it was reported that ibuprofen had few gastro-intestinal side-effects (Thompson and Anderson, 1970). However, bleeding ulcers have been recorded and diarrhoea is not uncommon (Lee et al., 1973). Transient elevation of serum glutamic pyruvic transaminase and alkaline phosphatase levels have been observed (Lewis, 1975). Central nervous system side-effects such as headaches, dizziness, lightheadedness, depression and fatigue, and skin rashes may occur; visual symptoms are very rare but are potential side-effects (Thompson , 1972). The usual recommended dose is 1,200 to 2,400mg per day. The authors do not recommend this drug until after a trial of aspirin in adequate doses. Its ultimate place in the treatment of rheumatoid arthritis will require additional years of clinical use; in the rheumatoid patient who refuses or cannot tolerate aspirin because of gastro-intestinal discomfort, a trial of ibuprofen or one of the other phenylalkanoic acid derivatives is indicated. Use in pregnant women or children is not recommended since studies in this respect are not completed. Calcium Fenoprofen (Fenoprofen) This is one of the newest phenylalkanoic acids. Preliminary studies indicate that like the other members of this group of compounds fenoprofen has a low toxicity and may have less gastro-intestinal and auditory side-effects than aspirin (Willkens and O'Brien, 1974) . In a double-blind clinical trial of 32 weeks involving 20 patients with rheumatoid arthritis at the University of Colorado, it was concluded that fenoprofen was comparable with aspirin as an antirheumatic agent and had the advantage of being less toxic (unpublished data). In a 16 week double-blind crossover study, Fries and Britton (1973) compared aspirin with fenoprofen in 27 patients with rheumatoid arthritis. The patients were given either 4g aspirin or 1.6g fenoprofen initially and were allowed to increase the dose if necessary to 6g aspirin or 2Ag fenoprofen. No significant differences were observed although aspirin appeared slightly more active. Low levels of side-effects suggested to the authors that higher doses of fenoprofen may be tolerated with greater benefits . Naproxen Naproxen is another new phenylalkanoic acid drug. It is more potent than aspirin in inhibiting prostaglandin biosynthesis, but less potent than indo-

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methacin in this regard. It has comparable therapeutic action to moderate doses of aspirin but causes fewer side-effects. Another advantage is its long half-life in serum requiring less frequent administration. The usual dose is 250mg 2 or 3 times a day.

CH3

I

CH-COOH

Naproxen

Flurbiprofen

H3 C -'CH-COOH

Ibuprofen

Q

Fenoprofen

o

6

Ketoprofen Fig. 4. Structural formulae of the phenylalkanoic acid derivatives commonly used in rheumatic diseases.

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Ketoprofen Ketoprofen is a phenylalkanoic acid available in the United Kingdom and some other countries, but only as investigational drug in the USA. In a doubleblind crossover study in 67 patients with rheumatoid arthritis comparing ketoprofen 150mg daily with indomethacin 100mg daily, Zutshi et al. (1974) found ketoprofen to be slightly less effective but to cause fewer side-effects. Flurbiprofen There are many more similar antirheumatic substances under trial, one of which, flurbiprofen, has had considerable clinical assessment. Results of initial therapeutic trials in rheumatoid arthritis suggest that flurbiprofen 100mg daily may be an effective substitute for aspirin at a total daily dose of about 3.6g (Laine, 1973; Owen, 1973, Barraclough et al., 1974).

5.2.4 Other Drugs with Mild Anti-Inflammatory Activity

Tolmetin This drug is not a phenylalkanoic acid and has a structural similarity with indomethacin. It is still an investigational drug in the USA. In patients with rheumatoid arthritis, tolmetin is effective in doses of about 1,200mg per day. It is said to be less ulcerogenic than indomethacin, but not absolutely free of this side-effect. Ehrlich (1973) reported its use in an open trial of 40 patients and found it effective and devoid of untoward effects in doses ranging from 600 to 1,800mg per day. Brooks et al. (1974) were unable to demonstrate a reduction in proximal interphalangeal (PIP) joint size or radioactive techenetium uptake in patients receiving 1,200 or 1,60Omg daily of tolmetin, although Brown et al. (1975) reported a significant decrease in PIP joint size after 2 months of therapy at doses of up to 1,400mg daily. Alclofenac Alclofenac, an arylacetic acid derivative related to ibuprofen, has, like the phenylalkanoic acids, proven itself a modest antirheumatic agent in the milder rheumatic conditions (Hart, 1975) . The analgesic and anti-inflammatory activity of alclofenac 3g daily in rheumatoid arthritis appears to be comparable with that of phenylbutazone 300mg daily (Aylward, 1973). Skin rash has been a relatively common side-effect early in treatment. In a long-term comparison of alclofenac 3 to 4g daily and indomethacin 150 to 200mg daily in 109 patients with rheumatoid arthritis, alclofenac was the more effective drug in producing clinical haematological and serological evidence of improvement (Aylward et a1., 1975).

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5.2.5 Anthranilic Acids This is another group of analgesics with mild anti-inflammatory activity which have been under clinical investigation. These compounds include flufenamic and mefenamic acid which have been available in some countries for many years, and meclofenamic acid which has been studied more recently .

Flufenamic Acid Rajan et al. (1967) found flufenamic acid to be 1.6 times as effective as phenylbutazone against ultraviolet induced rash in the guinea pig and 16 times as effective as aspirin. In the treatment of rheumatoid arthritic patients, flufenamic acid 600mg daily was indistinguishable from aspirin 3g daily and phenylbutazone 300mg daily. Mefenamic Acid Although this compound has been shown to be 5 times as effective as aspirin in the ultraviolet erythema test, at usual doses it is generally considered to be only an analgesic-antipyretic agent. Young (1963) found that in treating rheumatoid arthritic patients, 2,000mg mefenamic acid was comparable with 400mg oxyphenbutazone . Dizziness, nausea and diarrhoea were side-effects most frequently noted, the latter being the most disturbing. Meclofenamic Acid This drug was very promising in the preclinical trials. It was found to be 66 to 275 times more potent than aspirin in the ultraviolet erythema test, and in other animal tests it was only one-ninth as ulcerogenic as aspirin. In our Research Clinic, doses of 150mg per day have been effective in some patients with rheumatoid arthritis, but as with the other anthranilic acids diarrhoea has been a frequent complaint. The 150mg daily dose has been found to be equivalent to 3.6g of aspirin.

5.2.6 Antimalarials Chloroquine and hydroxychloroquine have been used extensively in treatment of rheumatoid arthritis. Although effective as antirheumatic agents, these drugs act slowly. Benefit is seldom evident in less than 3 months , and maximum improvement often requires 6 to 12 months. The usual dose is 250 to 500mg chloroquine (lor 2 tablets) per day or 200 to 400mg hydroxychloroquine (lor 2 tablets) . The incidence of side-effects is high. Side-effects include corneal opacities that are reversible upon stopping the drug. Recent emphasis has been given to irreversible retinal vasculitis. If antimalarials are used, ophthalmologic examinations every 3 months are recommended . The frequency of toxic reactions, some

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potentially serious, and the unpredictable and often slight benefits limit the value of these drugs in rheumatoid arthritis. 5.2.7 Intra-Articular Corticosteroids Intra-articular corticosteroids are useful when only a few joints are affected and when temporary relief of pain is desired. Another indication is to increase the benefit of physical therapy when one joint is inflamed out of proportion to the others, especially if the patient is hospitalised for a short period. A note of warning is necessary since an apparent flare-up of a single joint in this disease may be caused by a superimposed infection. The risk of introducing infection , although slight, is always present and proper aseptic technique is essential. Hydrocortisone acetate , prednisolone acetate or prednisolone tertiary butylacetate have all been shown to be effective. Frequent intra-articular corticosteroid injections may destroy the cartilage so most rheumatologists would agree that one or two injections may be given in a joint, but additional corticosteroid injections into that joint should not be repeated for at least 3 or 4 months. There is evidence that triamcinolone hexacetonide is the most effective long-acting steroid for intra-articular use, the effects lasting as long as 2 or even 4 months (Hollander, 1972).

5.2.8 Non-Narcotic Analgesics The most commonly used drugs of this type are paracetamol (acetaminophen) and dextropropoxyphene. When using these drugs, it is important to keep in mind that they are not anti-inflammatory. Because of this however, they can be used more safely in arthritics with peptic ulcers. They are indicated in rheumatoid stages III and IV when there is pain with little inflammation ; they are also used in earlier stages when anti-inflammatory drugs are contra-indicated due to gastro-intestinal complications. Narcotic drugs should not be used in chronic diseases as repeated use may lead to dependence.

Paracetamol This drug is usually considered to be a less potent analgesic than aspirin, 900mg being equivalent to about 600mg of aspirin. In rare instances, allergic reactions to paracetamol may occur. Dextropropoxyphene The analgesic potency of dextropropoxyphene remains controversial. Combinations of dextropropoxyphene with aspirin or paracetamol are more effective than dextropropoxyphene alone. Untoward reactions which limit its use include dizziness, nausea, vomiting and psychological dependence.

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5.2.9 Tranquillisers and Muscle Relaxants These drugs play a minor role in the therapy of rheumatoid arthritis. Anxiety frequently accompanies this crippling disease and may produce muscle contraction. Drugs such as diazepam or meprobamate which possess 'sedative' and muscle relaxant activity may be beneficial when used judiciously.

5.3 Treatment at Level 3 Among the forms of drug treatment making up the third level of the pyramid are oral corticosteroid therapy and gold therapy (fig. 3, level 2 and 3). Because of the side-effects of these agents, many experienced clinicians do not use them unless the drugs at the first two levelshave been tried and found to be ineffective. Other rheumatologists recommend using gold salts before corticosteroids and would place gold therapy first, among the forms of treatment at the second level. Gold therapy is not given unless the diagnosis of rheumatoid arthritis is well established. 5.3.1 Gold Salts Of all the anti-inflammatory and long-acting agents commonly used in treatment of rheumatoid arthritis, only gold salts may alter the clinical course or stop the progression of the disease. A rigidly controlled clinical trial in Great Britain (Empire Rheumatism Council, 1960) showed that gold salts were definitely useful in this disease, although at times the degree of benefit was not great. The preparations most frequently used are aurothioglucose and sodium aurothiomalate. These compounds are water-soluble and must be given by the intramuscular route. In the recommended dose schedule a small initial dose of lOmg is given to test for idiosyncrasy. If none is evident, 25mg is given one week later . The third and subsequent weekly doses are 50mg and these are given until a total of 1.0g has been administered. If no benefit is noted during this period of 4 to 5 months (800 to 1,000mg), the drug should be discontinued. If there is definite improvement after l g, the interval between injections should be lengthened to 2 weeks for several months and then further lengthened to 4 weeks. If benefit is sustained, monthly injections of 50rrig may be continued for periods ranging up to several years. It is our practice to discontinue gold after 6 more months of inactivity of the disease . The beneficial effects of gold therapy are gradual in onset, often becoming apparent after 8 to 10 weeks. Toxic reactions to gold are of the utmost importance. Those involving the kidney or bone marrow are potentially the most serious, and unless immediately recognised and treated , may even be fatal. The most common toxic manifestation is dermatitis, almost always preceded by pruritus. If gold is stopped temporarily when itching appears, the rash may be aborted or may be only mild

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and transient. Renal damage is evidenced first by albuminuria or microscopic haematuria. More than a trace of albumin or an abnormal number of red blood cells in the urine is a signal to interrupt therapy until the urine is again normal. The haematological changes can be the most serious and include thrombocytopenia, aplastic anaemia and agranulocytosis. Fortunately, these changes are rare, but may occur without prior warning. Gold therapy must be stopped whenever the white blood cell count drops below 4,OOO/mm 3 and should only be resumed (at half the usual dosage) if subsequent blood tests are normal. It is essential to obtain a blood count before each injection (including a count or estimation of platelets and eosinophils) and to interrupt therapy at the earliest evidence of toxicity. When serious reactions to gold have occurred in spite of these precautions , prednisone and dimercaprol (British Anti-Lewisite) have been shown to be highly effective in counteracting the toxicity. Penicillamine produces an 80-fold increase in the excretion of gold in the urine within 24 hours . Short courses of 3 to 7 days have been suggested to treat gold toxicity (Eyring et al., 1963).

5.3.2 Oral Corticosteroids The corticosteroids are the most powerful anti-inflammatory compounds available. However, their use in rheumatoid arthritis is controversial. There is no convincing evidence to show that corticosteroids stop or significantly alter the natural course of the underlying disease. They are used for their palliative effect in suppressing symptoms and alleviating general fatigue. They should not be used in an attempt to completely suppress the disease process. In deciding whether or not a programme of oral corticosteroid therapy is justified, one should consider the patient's economic situation , his need to continue working, the severity of the disease and the dose of the drug which may be necessary to achieve worthwhile improvement. Candidates for oral corticosteroid therapy are those patients who have severe unremitting disease with fever, anaemia, weight loss, effusions , neuropathy, vasculitis and deformities in spite of an adequate trial of treatment by more conservative means. After partial control of symptoms is achieved with a corticosteroid, the agent can be withdrawn gradually in some such cases. Other candidates are patients who are unable to carry out their regular household duties or to continue working at their jobs without small doses of corticosteroids. Such a patient may be a housewife, a breadwinner, or a single person living alone who would otherwise become dependent on relatives. Another use of corticosteroids is to provide 'steroid cover' for 4 to 6 weeks while awaiting possible beneficial effects of other agents, such as gold salts or an antimalarial. The dosage of corticosteroids used in attempts to accomplish the limited objectives should be kept as low as possible. Prednisolone or prednisone is the drug of choice. Initially, 5 or 7.5mg per day is given; the maximum daily dosage

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is 10 to 12mg and this is reached by increments of 2mg at intervals of four to seven days. None of the newer corticosteroids have any advantage over prednisone or prednisolone, and their greater potency makes dosage adjustment difficult. Few people can take therapeutic amounts of corticosteroids without some unwanted side-effects. These are dose-related, and serious ill effects are few when the dosage of prednisone or its equivalent is kept below 10mg per day. For withdrawal of a corticosteroid, a stepwise decrease in decrements of 1 or 2mg every 5 to 7 days is essential. Administration of corticosteroids on alternate days to minimise suppression of the pituitary-adrenal response is not recommended in arthritis since patients have pain on those days when the drug is omitted. To diminish adrenal suppression, the total daily dose should be given once a day using a short -acting corticosteroid (prednisone) and not fractionated . When an emergency or elective surgical procedure is necessary, it is usual practice to give a patient who is receiving a corticosteroid or has received corticosteroid therapy within the previous six months , supplementary doses of a corticosteroid parenterally immediately before the operation and afterward until oral medication can be resumed. There are many different schedules to prepare patients for surgery. The one recommended by Plumpton (1969) is as follows: On the day of surgery, give hydrocortisone hemisuccinate, 100mg 1M every 6 hours from the time of premedication , plus the usual maintenance dose of the corticosteroid. The same daily schedule is continued for the 3 first postoperative days. On the fourth day following surgery, the hydrocortisone is discontinued and maintenance doses of oral corticosteroids are again used. It is also advisable to have intravenous hydrocortisone available for quick administration during the surgical procedure if the blood pressure drops abruptly. Hydrocortisone hemisuccinate in doses of 100mg is recommended by the intravenous route any time signs of adrenal insufficiency occur . There is evidence to suggest that it may be more rational to observe the patient closely during and after surgery and to administer intravenous hydrocortisone only if a clear indication arises (Kehlet and Binder, 1973) . Many patients with rheumatoid arthritis have benefitted from cautious treatment with corticosteroids. A valuable tool is not discarded because it has a sharp edge, and adrenal corticosteroids are useful agents if properly used. We would be handicapped in our practice without the corticosteroids. 5.3.3 Adrenocorticotrophic Hormone (ACTH)

Rheumatoid arthritis patients have been treated for years with ACTH with good results, comparable with those obtained with oral corticosteroids (Savage et aI., 1959), but the inconvenience of repeated injections makes it impractical. Side-effects are similar to those which occur with systemic corticosteroids with the exception of suppression of adrenal function. Occasionally, severe allergic reactions to ACTH have been noticed .

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5.4 Treatment at Level 4 5.4.1 Hospitalisation There is a growing recognition of the value of 4 to 6 weeks of intensive hospital care for rheumatoid arthritic patients who do not respond to the measures already mentioned. The combination of intensive physical therapy and care by nurses with special arthritis training has been shown to alter favourably the otherwise progressive course of the disease. The benefits obtainable in hospital care units devoted specifically to arthritis treatment are clearly established.

5.5 Treatment at LevelS : Investigational Therapy New orthopaedic procedures and devices are being introduced, and the search for more effective and less toxic drugs continues . Until the results of careful studies define clearly the limitations and complications, any new agent or operative procedure must be considered experimental. Among the many promising drugs under clinical investigation are several 'immunosuppressive' or cytotoxic agents including cyclophosphamide, chlorambucil , and azathioprine ; others include D-penicillamine, histidine, dimethyl sulphoxide and radio-active gold. 5.5.1 Cyclophosphamide Fosdick et al. (1968) reported their experience in treating 54 rheumatoid arthritic patients with cyclophosphamide and indicated partial or complete remission in 75%. Before remission occurred, the white blood cell count fell to 2,000-4,000/mm 3 • These authors stated that no instance of fatal bone marrow depression was observed in their series. Later Fosdick (1969) reported complete remission of rheumatoid arthritis in 29 of 108 patients receiving cyclophosphamide, partial remission with laboratory confirmation in 45 , clinical remission without change in erythrocyte sedimentation rate in 21 and no response in 13. In 1970 these promising results were confirmed in part by a controlled clinical trial of cyclophosphamide in 48 patients (Decker and Mainland, 1970). The usual dose given at present is l.5mg/kg daily in two or three divided doses. A high incidence of dose-related side-effects has been reported. These include transient nausea, abdominal cramping and diarrhoea, hair loss in women , herpes zoster, haemorrhagic cystitis and amenorrhoea. A major unanswered question is the risk of induction of malignant changes. During the past 5 years at the University of Colorado Medical Center, 26 patients with rheumatoid arthritis unresponsive to conventional therapy have received cyclophosphamide for a minimum of 4 months and have been observed

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for at least 18 months. This controlled study , using objective measures, confirms the published observations and indicates that this antimetabolite suppresses joint inflammation in the majority of patients. The use of cyclophosphamide was interrupted temporarily in three of the cases because of leucopenia and in three others because of rash (1) , infection (1) and haemorrhagic cystitis (1). It was discontinued because of amenorrhoea in two young women . Five female patients had marked thinning of scalp hair but elected to continue receiving the drug, saying that the benefits made this side-effect acceptable. No renal, hepatic or carcinogenic toxic effect has been detected in this small series. Determination of erythrocyte sedimentation rate (Westergren) at 2-month intervals has not shown any consistent trend. Similarly , latex agglutination tests using tube dilution methods have shown no consistent change . 5.5.2 Azathioprine This drug, which is metabolised to 6-mercaptopurine , is the second most widely studied immunosuppressive agent used in rheumatoid arthritis. Azathioprine is administered orally in doses of 2 to 3mg/kg daily in divided doses. As with cyclophosphamide the benefits of treatment are often not apparent for 4 to 6 months or longer. In a recent controlled comparative trial of azathioprine , cyclophosphamide and gold in patients with relatively early, active , progressive rheumatoid arthritis, Currey et aI. (1974) concluded that the immunosuppressive drugs were better, especially azathioprine which necessitated fewer treatment withdrawals than the other drugs. However, a rather conservative gold regimen was used in this study . Use of the immunosuppressive drugs in rheumatoid arthritis should be restricted to patients in whom all forms of conventional treatment have failed to curb rapidly progressive disease with life-threatening complications. It is important to remember the old saying that 'potentially fatal treatment should not be used for a non-fatal disease unless there is a clear indication for it'. These drugs are still experimental and additional long-term studies will be required to establish their safety . 5.5.3 D-Penicillamine D-Penicillamine (3-mercaptovaline) has been used in the treatment of rheumatoid arthritis, especially in severe cases with vasculitis (Jaffe, 1965, 1969, 1970; Zuckner et al., 1970). Its use is limited by side-effects that are either a nuisance or hazardous. Nausea, vomiting and diminution of the sense of taste are amongst the nuisance group , whilst thrombocytopenia and proteinuria are more hazardous. This last effect may be indicative of immune-complex nephropathy and often occurs after many months of treatment. The drug is used in initial single daily doses of 250mg; if there are no side-effects, this is increased by 250mg every 15 days to reach a maintenance

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dose of 1 to 2g per day. The incidence of less serious side-effects may be reduced by a slower increase in dose to a maximum of 750mg daily, but proteinuria seems to remain as big a problem as with the higher dosage. White blood cell counts are necessary once a week during the first six months of therapy, and frequent urinalysis, as well as determination of serum creatinine and blood urea nitrogen. Platelet counts should be performed weekly for the first 4 weeks and monthly thereafter unless the count falls below 100,000. Reduction in dosage or temporary withdrawal of the drug is advisable if the count is below 70 ,000. In a recent multicentre trial comparing gold with D-penicillamine (Huskisson et al., 1974) there was little to choose between the efficacy of the two drugs. Both were highly effective in about 80% of patients with rheumatoid arthritis and there was no significant difference between them. Adverse effects were more common with D-penicillamine, but withdrawal of treatment was more frequent with gold therapy , mainly because of skin rashes. 6. Juvenile Rheumatoid Arthritis Salicylates are still the best treatment for juvenile rheumatoid arthritis. Since some children do not complain of much pain, a good guideline is to maintain a serum salicylate level of 20 to 30mgjl00ml, which is achieved usually with 90 to 130mgjkg in divided dosage daily (Calabro, 1972) . Caution is necessary however, as salicylism with signs and symptoms of acidosis is far more common in children than in adults and may be fatal if not recognised. Gold therapy is the second best choice and is the only treatment that may influence favourably the course of the disease. The usual dose is 0.5 to l mg/kg body weight once a week intramuscularly. The first dose is a smaller dose to test tolerance. Before every injection it is advisable to look for rashes, petechiae and scratching (pruritus) and to check the complete blood count (including platelets) and check the urine (especially for albumin) . In general, oral corticosteroids should not be used in children since extremely small doses will stunt growth. Exceptions are life-threatening situations, such as cardiac failure or eye complications as seen especially in pauciarticular arthritis. Usual doses are between 0.1 and OAmgjkgjday of prednisone. Intra -articular corticosteroids may occasionally be used. Phenylbutazone, antimalarials and the new non-steroidal anti-inflammatory drugs (sections 5.2.3, 5.204) are not indicated in children. Indomethacin is sometimes used in the United Kingdom but is not used in the USA. Immunosuppressive drugs should not be used in children in general because they are potentially very toxic drugs, and the treatment could be worse than the disease. They have only a symptomatic effect and may also stunt growth. However, in a very rare instance in which everything else has failed, and the patient has a poor prognosis, they might be of help.

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7. Ankylosing Spondylitis

Treatment of ankylosing spondylitis differs from that of rheumatoid arthritis in that gold therapy is not effective, and for this reason, is not used. In the past, radiotherapy localised to the spine was used with good response, but the increased incidence of post radiation malignancy has greatly reduced the use of this treatment, except in selected patients. Again, there is no drug that will alter the natural course of the disease, but patients treated with indomethacin, 25mg 3 or 4 times a day or phenylbutazone, 300 to 400mg per day in divided doses, experience real symptomatic improvement. We prefer indomethacin because it is devoid of bone marrow toxicity and, in most cases, does not produce fluid retention. Side-effects such as dizziness, headaches, nausea or rash, are infrequent or less severe if the initial dose is low (25mg) and given with the evening meal and then gradually increased as discussed in section 5.2.2. Exercises to counteract the tendency to produce rigidity and flexion contracture of the spine, as well as inextensibility of the thoracic cage, are essential.

8. Osteoarthrosis

There is no specific treatment for osteoarthrosis. The main concern in the treatment of this type of arthritis is to relieve pain , and for this goal, analgesics such as aspirin, paracetamol or dextropropoxyphene are indicated. The use of physical therapy measures such as heat and exercises, are a very useful adjunct in therapy . Recuperation of the key muscle of a joint (quadriceps for the knee or deltoid for the shoulder) relieves pain and corrects instability. Since there is little or no inflammation in joints affected by this degenerative type of arthritis , the role of anti -inflammatory drugs is limited. Aspirin and indomethacin or phenylbutazone are used in doses similar to or smaller than those used for rheumatoid arthritis, and only for a limited period. Oral corticosteroids should not be used since the side-effects outweigh the benefits in this condition. Intra-articular corticosteroids give relief, but do not alter the natural course of the illness; if over-used (more frequent than once every 4 months in same joint), they may accelerate destruction of the cartilage. Doses are the same as are used for rheumatoid arthritis and depend upon the size of the joint. The place in the treatment of osteoarthrosis of the phenylalkanoic acids, anthranilic acids and other new non-steroidal anti-inflammatory drugs is not well defined. In cases of secondary osteoarthrosis in which a primary cause is identified , correction of this factor may alleviate or stop progression of the disease. As an example of this, we have osteoarthrosis secondary to malalignment , obesity , shorter extremity, etc . In many cases, the primary cause even when known is not amenable to treatment , such as in mucopolysaccharidoses, ochronosis, etc.

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Nowadays, surgical procedures are of utmost importance in the treatment of osteoarthrosis. They vary from simple debridement of a joint to total joint replacement, in most cases with very good results.

9. Polymyalgia Rheumatica

Polymyalgia rheumatica (PMR), a disease that produces myalgia and arthralgias especially of the proximal joints (shoulder and pelvic girdle) and that is associated with a very high erythrocyte sedimentation rate (usually over 50mm , Westergren), is seen in older people usually over age 55. It mayor may not present itself with temporal arteritis; blindness may result as a complication . This illness responds so dramatically to corticosteroids that their administration is used as one of the confirmatory diagnostic criteria of PMR not associated with giant cell arteritis . Most cases will respond immediately or within the first 4 days to as little as l Orng of prednisone per day. If this dose is not initially effective the daily dose should be temporarily increased to 20mg, but gradually reduced to the lowest effective dose as soon as possible. Corticosteroid therapy needs to be prolonged for several months. If stopped too early, symptoms reappear and sedimentation rate rises. The prednisone should be tapered off slowly after having been given at a dose of l Omg daily for 2 months. Some patients require maintenance treatment for as long as 1 or 2 years. In cases with temporal arteritis, higher doses should be used (30mg or more daily) in order to prevent blindness. Other anti-inflammatory medications are not as efficacious as corticosteroids in this condition.

10. Adverse Reactions, Toxicity. Special Risk Patients

Principal adverse reactions of most of the individual drugs have been discussed already; here we would like to emphasise the potential ulcerogenic effect of all anti-inflammatory drugs. It is well known that aspirin, indomethacin and phenylbutazone are ulcerogenic. Glucocorticosteroids at low dose - i,e. l Omg prednisone or less daily - are considered by most rheumatologists to be less ulcerogenic than the above mentioned drugs in their usual doses. In order to minimise this tendency to produce peptic ulcers, these drugs should not be taken on an empty stomach . Antacids should be prescribed if the patient experiences gastro-intestinal discomfort with the drug or if he or she has a history of peptic ulcer. A well taken history and upper gastro-intestinal X-ray series are necessary in many cases to evaluate activity of ulcers before starting therapy . In patients with active ulcer, there is a need to stress the usefulness of frequent small meals, soft diet , milk and antacids as well as to select a less

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irritating drug. Paracetamol and dextropropoxyphene (section 5.2.8) are the analgesics to use if the patient has an active ulcer. Most anti-inflammatory agents would generally be contra-indicated in these patients. If pre-existing gastrointestinal problems are less serious, but the need of pain relief is great, low-dose corticosteroids may be used. Another step is the use of new anti-inflammatory drugs, such as ibuprofen or naproxen which are said to have less ulcerogenic potential. Buffered aspirins are better tolerated by the gastro-intestinal tract than plain aspirin. Benorylate seems to be less ulcerogenic than other aspirins, but is probably also less efficacious.

References Aylward . M.: Alclofenac in rheumatoid arthritis: An evaluation of its anti-inflammatory and analgesic effects . British Journal of Clinical Practice 27: 255 (1973). Aylward. M.; Parker, R.J.; Holly. F .; Maddock. J. and Davies. D.B.S.: Long-term study of indomethacin and a1clofenac in treatment of rheumatoid arthritis British Medical Journal 2: 7 (1975). Bain, L.S. and Burt. R.A.P.: The treatment of rheumatoid disease. A double-blind trial comparing buffered aspirin with benorylate . Clinical Trials Journal 7: 307-312 (1970). Barraclough, D.R.E.; Lenaghan , Elizabeth and Muirden, K.D.: A comparison of flurbiprofen and aspirin in the treatment of rheumatoid arthritis . Medical Journal of Australia 2: 925 (1974). Beales, D.L.; Burry, H.C. and Grahame, R.: Compar ison of aspirin and benorylate in the treatment of rheumatoid arthritis. British Medical Journal 2 : 483 (1972). Brooks, P.M.; Watkins, Caroline, F .; Sturrock, R.D. and Lee, P.: Clinical evaluation of tolmetin . Current Medical Research and Opinion 2: 323 (1974). Brown, J .H.; Hull, J. and Biundo, J.1 .: Results of a oneyear trial of tolmetin in patients with rheumatoid arthritis. Journal of Clinical Pharmacology 15: 455 (1975). Calabro, J.1.: Juvenile Rheumatoid Arthritis ; in Hollander (Ed .) Arthritis and Allied Conditions, p.387-402 (Lea & Febiger, Philadelphia 1972) . Chayen , J .; Bitensky, L. and Butcher , R.G.: Evidence for altered lysosomal membranes in synovial lining cells from human rheumatoid joints . Beitrage Pathology 142 : 137-149 (1971). Christian, C.L.: Immune-complex disease. New England Journal of Medicine 280: 878-884 (1969). Currey, H.L.F .; Harris, J .; Mason, R.M.; Woodland, J .M.; Beveridge, T.; Roberts , C.1.; Vere, B.W.; Dixon , A. St . J .; Davies, J. and Owen-Smith, B.: Comparison of azathioprine, cyclophosphamide and gold in the treatment of rheumatoid arthritis. British Medical Journal 3 : 763 (1974). Davidson, C.: Salicylate metabolism in man. Annals of New York Academy of Science 179: 249-268 (1971).

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Authors' address: Drs C.J. Smyth and I .F. Bravo, Arthritis Division, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220 (USA).