CYTOTOXIC THERAPY IN THE RHEUMATIC DISEASES: A REVIEW.

by drdoc on-line



There is a need to treat diseases at their source, and hence the introduction of cytotoxic and immunomodulatory therapy in the treatment of the Rheumatic Diseases. The use of these agents requires expertise and caution, in view of their potential side effects. Therefore strict indications and guidelines are required for their application.

THE IMMUNE RESPONSE.

With the introduction of antigen, Macrophages present processed antigen to Lymphocytes, which elaborate immunoregulatory substances, lymphokines, which result in Lymphocyte proliferation, B cell proliferation and differentiation into Plasma cells, and Antibody production. Complement activation and immune complex formation and deposition in tissues may occur. The net result is tissue damage. Intervention in the immune response can occur at several levels, by a number of agents. Several of these are applied in the treatment of Rheumatic disease.


CYTOTOXICS USED IN THERAPY OF THE RHEUMATIC DISEASES

1. Cyclophosphamide (Endoxan)
2. Chlorambucil (Leukeran)
3. Methotrexate (Rheumatrex)
4. Azathioprine (Imuran)


These have become increasingly used in the curative management of several life threatening Rheumatic diseases, in particular, the Necrotizing Vasculitidies such as Polyarteritis Nodosa (PAN), Wegeners granulomatosis (WG), Rheumatoid vasculitis, and also the Renal manifestations of Systemic Lupus Erythematosis (SLE). In general these drugs affect tissues with a rapid cell turnover, such as the bone marrow, mucosae, hair follicles, germ cells and fetal cells. The main clinical benefit is thought to be related to immunosuppressive activity, rather than the cytotoxicity of the agents. The latter, gives rise to the toxicity profile observed. (1,2)

CYCLOPHOSPHAMIDE.

Cyclophosphamide (CP), is an alkylating agent. It causes alkylation of the purine ring, and as a result, there is miscoding and blockade of DNA replication. CP is metabolized largely in the liver by the microsomal oxidative enzyme system, to cytotoxic products such as Phosphoramide Mustard and Acrolein. Immunosuppressive side chain products are also synthesized as part of the metabolic reactions, and include chloroacetaldehyde(1,2). These metabolites are largely excreted by the kidney. The pharmacokinetics of intravenous (IV) and oral administration are similar. Metabolites will accumulate in renal failure, and hence caution must be exercised in this situation. The agent is rapidly removed by haemodialysis. Drug interactions may occur by competition for, or induction of, the hepatic microsomal enzymes, especially by phenytoin and phenobarbitone. Toxicity is also enhanced by allopurinol and chloroquine, by uncertain mechanisms. The effect on the immune system, is mainly inhibition of the B cells, with reduction of antibody synthesis. The effect on T suppressor cells, results in an enhancement of the immunological response, seen with in-vitro studies. However clinically there is an overall state of suppressed immunity. The toxicity profile is summarized here...

CYCLOPHOSPHAMIDE: TOXICITY PROFILE.

1. MYELOSUPRESSION.
Leucopenia.
Thrombocytopenia.
2. URINE TRACT TOXICITY.
Heamorrhagic Cystitis.
Chronic Cystitis / Fibrosis.
Atypia / Malignancy.
3. RISK OF MALIGNANCY.
4. GONADAL DYSFUNCTION.
5. TERATOGENICITY.
6. RISK OF INFECTIONS.
7. NAUSEA.
8. ALOPECIA.
9. CARDIAC.
Cardiomyopathy.
Myocardial necrosis.
10. PULMONARY FIBROSIS.
11. HEPATOTOXICITY.
12. WATER INTOXICATION.
13. ALLERGIC PHENOMENA.
Rash.
Urticaria.
Anaphylaxis.

Myelosuppression: Suppression is maximal 8-10 days after a single dose of CP with full recovery occurring by 2-3 weeks. Stem cells are spared and recovery will occur. The aim of therapy is to maintain the granulocyte count above 1000/mm3, and the white blood cell count (WBC) above 3000-3500/mm3. The effectiveness of therapy is not however dependant on the WBC, but rather on the dose of CP. Excessive dosing will produce marrow toxicity. Monitoring of the full blood count (FBC) initially weekly for the first month and then monthly is recommended. The effect on the platelet count and red cell count is less than that on the WBC. Thrombocytopenia may occur with high doses of CP. The Platelet count should be maintained above 100000/mm3.
Urological and Bladder Toxicity: The major bladder side effects are felt to be attributed to the Acrolein metabolite of CP. Haemorrhagic cystitis occurs in 4-36% of cases. The condition may be mild , with dysuria and microscopic haematuria, or severe, with frank haematuria and haemorrhage. Cystoscopy and Intravenous Pyelography (IVP) are recommended. Local bladder cautery or Silver Nitrate instillation is given if haemorrhage is severe or does not respond to CP withdrawal. Failure of this to stop bleeding, may necessitate formalin 1-3% washouts under general anaesthesia. Rarely, cystectomy and urinary diversion is required. The haemorrhagic cystitis, has been shown to be prevented with the use of Sodium Mercaptoethane Sulphonate (Mesnum). Risk factors for cystitis include dehydration and elderly patients. Risk may be reduced by taking medication in the morning and drinking sufficient fluids, and frequent bladder emptying. IV administration, should be preceded and followed by saline infusions.(3,4,5) Bladder malignancies are observed rarely to occur. These frequently arise years after withdrawal of CP. Thus persistent urological symptoms must be investigated.(6) Other malignancies: Leukaemia, Lymphoma and cutaneous malignancies are described to occur. These are usually seen in patients on high dose therapy for prolonged periods.(7)
Gonadal dysfunction: This is associated with loss of the seminiferous tubules and results in reduction of the spermatozoa count. In females, ovarian fibrosis may result in amenorrhoea. Recovery may not occur, with infertility a consequence.(1,2) Teratogenicity: No definite syndromes are described, however fetal deformities are reported and contraception and counselling are essential in patients at risk.(8,9)
Infections: These occur frequently and most commonly are Gram negative organisms, including enterobacteriae especially pseudomonas, but staphylococcal infections and opportunistic organisms such as pneumocystis carinii, and viral infections especially herpes are commonly reported. Infection sites are most likely, lung, skin, and urinary tract. Risk of infection is greatest in leucopenia, aged patients, high dose therapy, corticosteroid use, and catheter placements or surgical procedures.(10,11)
Gastrointestinal problems: with nausea and vomiting may be eased by usage of metoclopramide (maxolon) or prochlorperazine (stemetil) or related drug.
Alopecia: Alopecia is dose related, and may be prevented with a scalp tourniquet during IV administration. The side effect is reversible.
Myocardial necrosis and cardiomyopathy, respiratory and hepato-toxicity: are reported but rare and dose dependant.
Allergy: Allergic phenomena include rashes, urticaria and anaphylaxis.

CHLORAMBUCIL.

Chlorambucil, like CP, is an alkylating agent. Absorption orally is rapid. Metabolism occurs to form phenylacetic acid mustard, and other less well defined metabolites. Excretion of these occurs into the urine. Toxicity profile is similar to CP, with marrow suppression, alopecia, azoospermia, anovulation, nausea, risk of infections and neoplasia. However the bladder toxicity does not occur.

METHOTREXATE.

Methotrexate (MTX) is a dihydrofolate reductase inhibitor. Folate reduction to folate cofactors is prevented, and purine nucleotide production is inhibited, with thymidilic acid and inosinic acid production impaired. Cells of rapid turnover are most susceptible to the agent. There is also some direct antiinflammatory action, but the mechanism for this is uncertain. The drug is well absorbed and is concentrated in the liver and biliary tract. There is a considerable enterohepatic recycling in it's metabolism. Absorption may be impaired by an enteropathy, and the D-Xylose absorption test has been shown to correlate with MTX absorption. The test can be used to exclude malabsorption if oral therapy has failed. 70% of MTX is protein bound and drug interactions, for example with sulphonamides, or nonsteroidal antiinflammatory agents may occur, that displace it from the protein and enhance the toxicity. High doses of folic acid can interfere with the activity of MTX and reduce the therapeutic benefit.(12,13) The main toxicity profile is illustrated below....

METHOTREXATE: TOXICITY PROFILE.


1. BONE MARROW SUPPRESSION.
2. HEPATOTOXICITY.
fibrosis.
cirrhosis.
3. PULMONARY TOXICITY.
acute pneumonitis.
interstitial pneumonitis.
interstitial fibrosis.
4. NEPHROTOXICITY.
5. INFECTIONS.
6. ORAL ULCERS.
7. NAUSEA / DIARRHOEA.
8. ALOPECIA.
9. TERATOGENESIS.

Hepatotoxicity: The incidence is related to total dose of MTX. In addition, frequency of administration, i.e daily, as opposed to a weekly regimen enhances risk. The presence of large pleural effusions or ascites, act as drug reservoirs, and prolong time of exposure to the drug and are also associated with greater hepatic problems. A cumulative total dose of greater than 2 grams, results in a significant increase in the incidence of cirrhosis. Most authors suggest a liver biopsy every 1-1.5 grams cumulative dose. The presence of early fibrosis, calls for more frequent repeat biopsies. If severe fibrosis is found, the MTX should be stopped. Whilst cases of cirrhosis have been found in psoriasis patients on MTX, no cases as yet have been described in Rheumatoid arthritis (RA) patients. This may be due to the lower doses generally used for the latter. The risk of cirrhosis is enhanced in diabetics, excessive alcohol consumers, obese patients, and patients with underlying liver disease. Pulmonary toxicity: An interstitial pneumonitis is well documented to occur, and patients with an acute pneumonitis, pulmonary infiltrates, and frequently peripheral eosinophilia, have been reported. Treatment, with MTX withdrawal and corticosteroid is usually effective. Interstitial fibrosis may occur and hence baseline Chest X-ray is advisable, to assist in differentiating this from the underlying disease process itself.
Marrow suppression: is well documented and largely dose dependant. The toxicity can be reduced by citrovorum factor, which provides folate in reduced form.
Teratogenicity: The possibility of toxicity to the fetus is well known and is seen in up to 30% of patients. There is a high incidence of spontaneous abortion. Most authors advise therapeutic abortion to patients who become pregnant on MTX. Lactation is also prohibited, as the drug is secreted into breast milk.
Neoplasia: MTX is not thought to predispose to malignancy.
Infections: In view of the effects on immune function, there is an increased risk of infections both by conventional organisms as well as opportunistic organisms and also viral and mycobacterial infections.

AZATHIOPRINE.

Azathioprine (AZA) is a purine analogue that prevents de novo synthesis of adenine and guanine. It is metabolized to 6 Mercaptopurine, 6 Thiosinic acid and 6 Thioguanylic acid. The latter two metabolites are cytotoxic. The metabolism of AZA, requires xanthine oxidase and hence allopurinol causes enhanced drug levels, by competing for the enzyme and preventing innactivation. The drug suppresses both the primary and secondary immune response if administered after antigen exposure. It has a significant effect on immunoglobulin levels. There is also marked suppression of natural killer cell activity. Lymphopenia is only rarely seen. The overall effect on the immune system is less than that of CP and chlorambucil. The toxicity profile is also less than that seen with the other agents, with bone marrow suppression, infections, and gastrointestinal intolerance. There is in addition, a risk of a hypersensitivity hepatitis with cholestasis. Treatment consists of drug withdrawal, and it is usually reversible. Teratogenicity is not seen, although use in pregnancy remains undesirable if possible. The risk of malignancy is not reported at doses used in the treatment of the rheumatic diseases, although it is reported in transplant patients treated with AZA. Reproductive failure is also not a problem with AZA.


GUIDELINES FOR THE USE OF THE CYTOTOXICS.

A number of precautions and guidelines are proposed in the use of the cytotoxics(14) ............

SPECIAL PRECAUTIONS IN THE USE OF CYTOTOXIC DRUGS.

1. Correct indication for use.
2. Potentially fatal disease or significant morbidity.
3. Potential for reversibility.
4. Set goal of therapy.
5. Consider a sufficient time for effect.
6. Define failure of therapy.
7. Discontinue if therapy fails.
8. Use conventional first line therapy where possible.
9. Full explanation to the patient concerning reasons for use.
10. Monitor disease activity and progress of therapy.
11. Monitor for side effects and adjust dose as required.
12. Counsel regarding pregnancy / contraception.
13. Avoid live vaccinations.

It is essential that the patient understands the significance of the drug and the disease itself.
Monitoring to prevent and detect complications of specific therapy, are illustrated here...

Monitoring and Precautions:

Cyclophosphamide.

1. FBC 1-2 weekly initially and then monthly once disease stable.
2. Urinalysis 1-3 monthly.
3. Adequate fluids with administration.
4. Void bladder frequently with administration.

Chlorambucil.

1. FBC 1-2 weekly initially and then monthly once disease stable.

Methotrexate.

1. FBC 1-2 weekly initially and then monthly once disease stable.
2. Aspartate and Alanine transaminases (AST & ALT) 1-2 monthly.
3. Gamma Glutamyl transferase 1-2 monthly.
4. Baseline Creatinine clearance. Urea, Creatinine, 6 monthly.
5. Baseline Chest X-ray.

Azathioprine.

1. FBC 1-2 weekly initially and then monthly once disease stable.
2. AST & ALT & Gamma-GT 6 monthly.


THE CLINICAL APPLICATION IN THERAPEUTICS OF THE RHEUMATIC DISEASES.

RHEUMATOID ARTHRITIS:
ARTICULAR INVOLVEMENT. Methotrexate has been increasingly used in RA, with effectiveness demonstrated with oral doses of 7.5-15 mg given weekly. The effect is more rapid than the standard second line Disease Modifying Agents (DMA's), such as Gold, Penicillamine, Sulphasalazine and the Antimalarials. A response is seen in 3-6 weeks, with a maximal response by 4-6 months and a plateau effect demonstrated. Improvement in morning stiffness, joint pain, tenderness and activity scores, is noted in 66% of patients. MTX used weekly IV, has also demonstrated efficacy in uncontrolled and retrospective studies. At low doses of MTX, the toxicity has not been worse and may even be better than standard DMA's. Between 66-86% of patients are still using MTX after 53 months, and the majority (90%) of side effects are mild. Large double blind studies are still awaited. In the interim, it is recommended that the drug be used in patients not responsive to standard second line agents, and is the immunosuppressive of choice.(15) AZA has been demonstrated to produce a clinical response in doses ranging from 1-3 mg/kg/day. Some studies have shown reduction in progression of erosions, but this has not been confirmed in other studies. It would appear however, that risk of side effects, in particular, risk of malignancy, make AZA only advisable, if conventional therapy has failed, despite a good trial of therapy for 4-6 months at full dosage. Cyclophosphamide similarly has been shown to have a significant benefit in control of synovitis and also a reduction in erosion development. Studies of both intravenous "pulse" therapy and oral therapy 1.5-2 mg/kg/day confirm this. However the risk, precludes early use, and CP is reserved for patients non responsive to less toxic medications. (16,17,18,19,20) Chlorambucil has been used in some trials, with benefit in 50-75% of patients, but again is felt to be too potentially toxic for general or early usage.

RHEUMATOID ARTHRITIS:
EXTRA-ARTICULAR INVOLVEMENT. There is a clear role for cytotoxic medications in several extra-articular problems identified with RA. Rheumatoid vasculitis is increasingly identified as a disease of high morbidity and mortality.(21,22,23) The 5 year mortality is 60% versus 90% of the general RA population. The presence of periungual infarcts, is not on it's own an indication for aggressive therapy. However vasculitis with severe ischaemic skin lesions, neuropathic involvement such as mononeuritis multiplex, and organ involvement, calls for urgent immunosuppressive therapy. The standard recommended therapy is that of intermittent IV "pulse" therapy as outlined here...(22)

PULSE INTRAVENOUS METHYLPREDNISOLONE AND CYCLOPHOSPHAMIDE THERAPY FOR RHEUMATOID VASCULITIS.(22)

DAY

1

8

29

50

METHYL PREDNISOLONE IVI

500mg

1000mg

1000mg

1000mg

CYCLOPHOSPHAMIDE IVI

500mg

15mg/Kg

15mg/Kg

15mg/Kg

This combination of methyl prednisolone and cyclophosphamide, has improved morbidity, mortality, and risk of relapse. Each is given sequentially as an infusion in 200 ml of normal saline over 30 minutes. Thereafter, repeat doses are given after one week, and then twice more, two weeks apart.(22) AZA has not proven beneficial in the treatment of RA vasculitis, whilst CHLOR has been shown to be efficacious, but less preferred in view of greater malignancy risk. Severe scleritis, should be treated with corticosteroid in the first instance, with the addition of immunosuppressive therapy, such as oral CP 1.5 mg/kg/day if required. Progressive pulmonary interstitial disease of RA, may be treated with immunosuppressive therapy if no response to corticosteroid is seen, or as a steroid sparing agent, to minimize complications of high dose steroids.

SYSTEMIC LUPUS ERYTHEMATOSUS.
Cytotoxic or immunosuppressive therapy is indicated for severe life threatening disease, especially for proliferative nephritis, with class 3 or class 4 histological types, or heavy proteinuria with an active urine sediment.(24-30) Treatment may also be indicated for treatment of severe haemolytic anaemia, thrombocytopenia, organic brain disease and vasculitis affecting major organs, where steroid therapy has caused unacceptable side effects, or the dose required is too high, or there is no response.(31) AZA may be used at 2-3 mg/kg/day orally in combination with corticosteroid. CP is felt to be superior to AZA and is the immunosuppressive of choice. CP has shown benefit when used together with oral corticosteroid, either as oral CP 1.5-2 mg/kg/day, or, 1 or 3 monthly (0.5-1 g/m2) IV pulses, especially for severe renal involvement. Oral CP used alone at the onset of treatment, has not been shown to be beneficial. Further controlled studies are awaited. We would recommend combination of prednisone 1 mg/kg/day, plus oral CP 1.5 mg/kg/day, with rapid weaning of steroid to an alternate day regimen by 6 months. If the disease is stable, steroid withdrawal may then be attempted. In very severe disease with proliferative nephritis and crescents, a single pulse of intravenous CP and methyl prednisolone may be considered, followed by oral therapy. In general immunosuppressive therapy is continued for 1-2 years, and then withdrawal may be attempted. A patient in established end stage chronic renal failure is not a candidate for cytotoxic therapy if the process is irreversible.

PSORIATIC ARTHROPATHY.
MTX is the immunosuppressive agent of choice in severe active arthropathy. Higher doses are usually required than those used in RA. Starting dose is 7.5-10 mg/week, increasing every 1-2 months to a maximum of 50 mg/week if no response is found. The skin lesions are also improved. Response is usual by 2-3 months.(12) AZA may also be used, 2 mg/kg/day, increasing slowly to 3-3.5 mg/kg/day, if required.

REITERS SYNDROME.
MTX is efficacious for severe Reiters syndrome at dose 12.5-25 mg/week. Improvement is rapid, within 2-8 weeks. The agent should be restricted to severe disease, not responsive to conventional anti-inflammatory drugs.12

POLYMYOSITIS / DERMATOMYOSITIS.
Immunosuppressive drugs are indicated if conventional corticosteroid therapy fails, or if unacceptable side effects occur. In addition, they may have a place if life threatening disease complications are present, such as cardiac or respiratory failure. AZA 1.5-3 mg/kg/day has been observed in uncontrolled studies to improve function at 3 years, when used with steroids, and is better than steroids alone. The AZA dose can be reduced once the disease stabilizes, to 50 mg/day. MTX is currently felt to be the first immunosuppressive agent of choice and can be used either orally or IV. Oral dosage is 7.5-10 mg/week, increasing by 2.5 mg/week up to a maximum of 20-25 mg/week. IV regimen is 10 mg/week, increasing to 0.5-0.8 mg/kg/week. The agent is continued until the disease is fully controlled, then the dose may be reduced by 25% of total dose, to a lower maintenance dose. Alternatively, the frequency of administration may be reduced, initially fortnightly and then monthly. Steroid doses should be reduced once the immunosuppressant is commenced.(12,32,33) CP and CHLOR are only used in refractory disease in view of their side effect risk.

SYSTEMIC SCLEROSIS.
Whilst no drug has proven to be of consistent benefit as a disease modifying agent, CP, CHLOR, or AZA may be tried in rapidly progressive or life threatening disease.

SYSTEMIC NECROTIZING VASCULITIS.
The therapy of these conditions, has been revolutionized, with the combination of corticosteroids and immunosuppressive medications. A definite role is seen in the treatment of vasculitis of medium size arteries, such as Polyarteritis Nodosa (PAN), Wegeners granulomatosis (WG), Allergic granulomatous angiitis, as well as the vasculitis of SLE and RA.(34-38) The role in large vessel vasculitis, such as Takayasu arteritis is less well defined. There is not felt to be a role in the treatment of small vessel vasculitis such as hypersensitivity vasculitis. Wegeners granulomatosis, has a mortality of 90% untreated. Steroid therapy improves survival to 48%. Treatment with CP increases survival to 90%. Treatment with CP alone appears as effective as with combination with corticosteroid. Experience with AZA, demonstrates a role in maintenance therapy, but a poor role in the induction of remission. It is the drug of second choice. The recommended regimen in therapy of WG, depends on disease severity. For mild disease, CP 1-2 mg/kg/day, increasing by 25 mg every 2 weeks until a clinical response or toxicity is seen. The WBC should be maintained between 3000-3500/mm3 and granulocyte count greater than 1000/mm3. In severe disease, or acutely ill patients a loading dose of intravenous CP of 4 mg/kg may be given for 2-4 days and then oral therapy commenced in standard doses. Prednisone, 1 mg/kg/day should be given for moderate to severe disease with rapid reduction, aiming at withdrawal by 6 months. CP itself should be continued for 12-18 months following complete remission. If AZA is used, recommended dose is 2-3 mg/kg/day, with therapy for 12-18 months following complete remission. Polyarteritis Nodosa, has a similar prognosis and benefit to WG when treated with CP and steroids. A similar drug protocol is recommended. Most authors recommend use of prednisone combined with CP for the treatment of PAN. Allergic Granulomatous Angiitis has a 5 year survival of 10%. Benefit has been shown with corticosteroid, which improve prognosis to a 50% 5 year survival. Although few studies have been done with immunosuppressive therapy, it is generally recommended that they be used if renal involvement is present.

BEHCETS SYNDROME.
There is some evidence that CHLOR may be useful in preventing ocular damage when used with prednisone, and that this benefit is greater than prednisone alone.


CONCLUSION

Many problems exist with the trials on cytotoxic therapy. These relate to the fluctuant course of the diseases and the small number of patients involved. There is difficulty setting up controlled trials, with consistency of drug doses. Nevertheless, clinically, it would seem appropriate to restrict their use to severe disease and to those patients who have failed to respond to less toxic therapy, where that therapy is available and efficacious(14,39). Skill and experience is required with their use, and a great respect for their potential problems is essential


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Original Article -copyright
Dr D Gotlieb. FCP (SA).
Rheumatologist
Constantiaberg Medi-Clinic
Cape Town
South Africa


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