Cyclosporine

in Rheumatoid

Arthritis

By B.A.C. Dijkmans, A.W.A.M. van Rijthoven, H.S. Goei The, M. Boers, and A. Cats The efficacy and toxicity of cyclosporine in the treatment of patients with rheumatoid arthritis (RA) are reviewed. Most of the early trials were restricted to patients with intractable RA. The initial daily dose of cyclosporine was 5 to 10 mg/kg, which is now considered high. Of 283 cyclosporine-treated patients in nine studies, 8% discontinued the drug prematurely because of inefficacy and 17% because of adverse reactions. Cyclosporine improves clinical parameters but does not influence the erythrocyte sedimentation rate. The most important side effects

I

N THE TREATMENT of rheumatoid arthritis (RA), two classes of drugs can be distinguished: nonsteroidal antiinflammatory drugs (NSAIDs) and drugs claimed to induce a remission of the disease. The latter are called diseasemodifying drugs, remittive agents, or secondline drugs. Examples are antimalarial& sulphasalazine, oral and parenteral gold, D-penicillamine, corticosteroids, and cytostatics such as methotrexate and azathioprine. Only a portion of patients with active RA react favorably to these drugs. Moreover, the frequency and severity of side effects are considerable. Therefore, new types of remittive agents are needed. During the 1980s several studies were conducted to investigate the efficacy and toxicity of cyclosporine in RA. Past experience has shown that a 5-year period of trial and error is inadequate to study a drug adequately. For example, sulphasalazine became a forgotten drug until the 1980s despite its short-lasting success in the From the Department of Rheumatology, Leiden University Hospital, Leiden; Department of Rheumatology, Deaconess Hospital, Eindhoven; and Depariment of Rheumatology, De Wever Hospital, Heerlen, the Netherlands. B.A.C. Dijkmans, MD: Department of Rheumatology, Leiden University Hospital; A.W.A.M. van Rijthoven, MD: Department of Rheumatology Deaconess Hospital, Eindhoven; H.S. Goei Tht, MD: Depattment of Rheumatology, De Wever Hospital, Heerlen; M. Boers, MD: Department of Rheumatology, Leiden University Hospital; A. Cats, MD: Department of Rheumatology, Leiden UniversityHospital. Address reprint requests to B.A.C. Dijkmans, MD, University Hospital, Department of Rheumatology, Building I, CZ-Q, PO Box 9600, 2300 RC Leiden, the Netherlands. Copyright 0 1992 by W.B. Saunders Company 0049-0172/92/2201-0004$5.00/O 30

are gastrointestinal intolerance and nephrotoxicity. The former is of minor importance with the present dosage schedule (starting daily dose, 2.5 mg/ kg), and increments should follow the principle “go low, go slow.” Guidelines are given to avoid or reduce nephrotoxicity. It may be beneficial to administer cyclosporine early in the course of RA. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: arthritis.

Cyclosporine;

rheumatoid

1940s. On the other hand, methotrexate, a “&ord” in the 1950s was “recast” as a “plough” in the 1980s. In this article we attempt to balance the efficacy and toxicity of cyclosporine in the early 1990s and make suggestions for future work.

POTENTIAL ACTIONS OF CYCLOSPORINE IN RA

Cyclosporine inhibits T-lymphocyte activation and proliferation. 1,2It selectively inhibits both antigen-induced activation of CD+ (Thelper) lymphocytes and production by these cells of interleukin-2 and other cytokines.le4 Cyclosporine can also interrupt active immune responses, as shown by its efficacy in treating autoimmune diseases, presumably by blocking the secretion of cytokines by lymphocytes.3 The drug inhibits the in vivo transcription of genes encoding interleukin-2 and interferon-y and blocks the expression of interleukin-2 receptors, whose induction is essential to T-cell proliferation.3,4 It is now clear that cyclosporine reversibly inhibits early, calcium-dependent events in T-lymphocyte activation and that there are probably several molecular targets within the cell membrane, cytosol, and nucleus.3g4 The most exciting new developments concern the uptake and concentration of cyclosporine in cystolic and nuclear target sites mediated by cyclophilin, a recently discovered enzyme.3,4 In view of its molecular action, which has been described in many studies and was recently reviewed in depth,‘-ls not surprisingly cyclosporine will induce and maintain remission in many

Seminars in Arthritis andRheumafism,

Vol 22,

No 1 (August), 1992: pp 30-36

CYCLOSPORINE

31

IN RA

autoimmune disorders, particularly mechanisms mediated by T cells.

those with

Table 1: Spontaneous Autoimmune

and Experimental

Diseases in Animals Wherein

Cyclosporine Proved Efficacious

Cellular Immunity in RA

In RA there is also abundant evidence for the involvement of T cells.19 Experimental arthritis, eg, induced by immunization against collagen20 or adjuvant, is clearly T-cell driven and can be induced by specifically sensitized T cells.*’ Immunohistology of the synovium in patients with RA shows many DR+ macrophages, dendritic cells, and synovial fibroblasts with T cells in close apposition.** Fourty-five percent to 90% of the T cells in synovial fluid are activated (DR+) and express the cell surface phenotype of helper or cytotoxic cells.23 There is a virtual absence of suppressor-inducer T cells and a marked increase in helper-inducer T cells in the rheumatoid synovial fluid.24,25As in the synovial membrane, there is evidence for T-cell activation in synovial fluid. 26Almost all the currently available data support the hypothesis that there is an overactivation of lymphocytes and that this overactivation is directed more toward helper than toward suppressor T cells.19 Based on these observations, there is a clear rationale for the use of cyclosporine in RA. Cyclosporine in Autoimmune Diseases

Apart from the above-mentioned considerations, the other arguments for the administration of cyclosporine in RA are derived from its use both in animal models of autoimmune diseases and in autoimmune diseases in humans. An overview of autoimmune diseases in animal models, both spontaneous and experimental, wherein cyclosporine has proved to be efficacious is shown in Table l.*’ The use of cyclosporine remains experimental because of its toxic effects and the relatively immediate relapse after discontinuation of therapy. The rationale for the administration of cyclosporine depends on the role of T-cell immunity in the specific autoimmune disease. Such a disease is uveitis, in which T-cell immunity and delayed hypersensitivity play an important role; cyclosporine is reported to have considerable therapeutic efficacy.28 On the other hand, in systemic lupus erythematosus humoral immunity may be more important than cellular

Experimental Disease Adjuvant

arthritis

collagen Allergic

Species Rat

Rheumatoid

Rat, guinea pig,

Multiple

II

enceph-

Human Correlate arthritis

alomyelitis

rhesus

sclerosis

monkey Uveitis

Rat

Uveitis

Myasthenia

Rat

Myasthenia

BB rat

Diabetes mellitus

NZBIWF

Systemic

gravis Spontaneous

gravis

diabetes mellitus Spontaneous lupus

mouse

lupus

erythematosus

Data from Thomson et al.*?

immunity; therefore, there is less rationale for the use of cyclosporine in this disease, and nonrandomized studies suggest that the effect of cyclosporine in systemic lupus erythematosus is not striking.29 Psoriasis responds to doses as low as 3 mg/kg/d,30 possibly because the drug inhibits keratinocyte proliferation. When the treatment of adult-onset31 and juvenile-onset32 diabetes mellitus with cyclosporine begins within 2 months after the initiation of insulin therapy, the latter can often be withdrawn for some months. Minimal-change focal and segmental, membranous, and IgA nephropathies, which can be treated with other immunosuppressive agents, are also sensitive to cyclosporine3”; however, it is uncertain whether the reduction in proteinuria reflects healing of the basement membrane or a decrease in the glomerular filtration rate. Therapy with cyclosporine has recently been reported promising in several other diseases such as precirrhotic primary biliary cirrhosis,34 myasthenia gravis,35 and chronic active hepatitis.j6 CLINICAL

STUDIES

OF CYCLOSPORINE

IN RA

In the first study of cyclosporine in polyarthritis, a beneficial effect on the activity of the disease was seen in three of five patients.37 In the last 5 years, several controlled clinical trials of cyclosporine in RA have been completed.38-48

32

DIJKMANS ET AL

Table 2: Studies of Cyclosporine in Rheumatoid Arthritis Patients Mean

Mean

Starting

Type of

Age of

Disease

Daily Dose

Study

Rheumatoid

Patients

Duration

of Cyclosporine

Duration

(vr)

(vr)

(mg/kg)

(wk)

54

12

10

26

(SD, 12.9)

(SD, 6.2)

Open

54

12

6

24

Open, compared with

53

4

10

26

Study Van Rijthoven et al

Arthritis

Study Design

Intractable

Double-blind,

(1986)38

placebo-

controlled

Weinblatt et al (1987)3g

Intractable

F@rre et al (1987)40

azathioprine Tugwell et al (1987)41

Advanced

Open

Dougados et al (1988)43

Double-blind,

placebo-

controlled Yocum et al (1988)U

Intractable

Double-blind,

Tugwell et al (1 990)46

high-low-

Open Severe

Placebo-controlled

van Rijthoven et al

Double-blind, compared with o-penicillamine

(1991)4’

(SD, 4.1) 13

10

26

58

8

5

16

10

24

(median)

dose cyclosporine

Dougados et al (1987)45

(SD, 12.3) 58

These trials are summarized in Tables 2 and 3. Most of the early trials were restricted to patients with intractable FU. The mean age of the patients was generally between 50 and 60 years, and the mean disease duration exceeded 10 years. The initial daily dose of cyclosporine was 10 mg/kg in the early trials; more recent trials have used lower dosages. The duration of

(median)

49

14

(SD, 8.5)

(SD, 5.4)

50

11

(SD, 8.4)

(SD, 6.4)

55

14

(SD, 11.9)

(SD, 9.9)

54

11

(SD, 1.2)

(SD, 0.9)

57

1

6

(SD, 10.0)

5

52

2.5

26

5

24

(SD, 6.8)

each trial was long enough to achieve efficacy if present. Four of these studies were open39-41,45; the remaining ones were controlled.38,43,44,46,47 The balance between adverse reactions and efficacy is shown in Table 3. Of 283 cyclosporinetreated patients, 22 (8%) stopped the drug prematurely because of inefficacy. Premature discontinuations because of inefficacy occurred

Table 3: Adverse Reactions and Efficacy With Cyclosporine in Rheumatoid Arthritis Patients Premature Efficacy

Discontinuations Adverse

Clinical

Inefficacy

Reactions

Parameters

Number of Study

Patients

ESR

van Rijthoven et al (1986)%

17

1 (6%)

7 (41%)

Effect

No effect

Weinblatt et al (1987)3g

10

2 (20%)

2 (20%)

Effect

No effect

Ferre et al (1987)40

12

0 (0%)

2 (17%)

Effect

ND

Tugwell et al (1 987)41

20

1 (5%)

4 (20%)

Effect

No effect

Dougados et al (1988)43

26

0 (0%)

4 (15%)

Effect

No effect

Yocum et al (1988)44

15 (high)

0 (0%)

3 (20%)

Effect

No effect

16 (low)

4 (25%)

3 (19%)

Effect

No effect

Dougados et al (1989)45

49

10 (20%)

11 (23%)*

Effect

No effect

Tugwell et al (1990)46

72

3 (4%)

4 (6%)

Effect

No effect

van Rijthoven et al (1 991)47

46

1 (2%)

9 (20%)

Effect

No effect

283

22 (8%)

49 (17%)

Total Abbreviations:

ESR, erythrocyte sedimentation rate; ND, not done or not mentioned.

*Nine patients were withdrawn because of inefficacy and toxicity.

CYCLOSPORINE

IN RA

slightly more frequently in studies with lower dosages than in those with higher dosages of cyclosporine. The findings in regard to clinical and laboratory parameters are roughly similar in all the studies. Clinical parameters such as number of swollen joints, Ritchie articular index, and pain scores improved significantly between the start and the end of the studies, while improvement in laboratory parameters was absent or less impressive. The erythocyte sedimentation rate (ESR) did not change in any study, and the titer of rheumatoid factor decreased only in one study.40 C-reactive protein concentration decreased in the majority of the studies in which it was determined.40,43T44Apparently the ESR is not a good parameter for measuring the effect of cyclosporine on inflammation. The finding of lack of change in ESR despite clinical improvement is not only seen in RA but also in uveitis; in the latter disease there is a clear trend toward an increase in ESR in cyclosporinetreated patients.49 The beneficial effects of a drug must be weighed against its adverse reactions. The frequency of side effects is high, up to lOO%, depending on the definition of an adverse reaction. The most important side effects are gastrointestinal intolerance and impairment of renal function. When an increase in serum creatinine is considered an adverse reaction, the frequency of side effects reaches almost 100%. Gastrointestinal intolerance was a major problem in the early studies using a high daily dose (10 mg/kg body weight) but is less so with lower dosages. However, the percentage of gastrointestinal side effects is high (50% to 75%) even with lower dosages.41,43 The major reasons for premature discontinuations were adverse reactions in 49 (17%) ranging from 6% to 41%, of the 283 cyclosporine treated patients (Table 3). The percentage of premature discontinuations because of adverse reactions in the study with the highest number of patients was 6%.46 Because the dosage of cyclosporine was only 2.5 mg/kg/d with a stabilization dose of 3.8 mg/kg/d in that study, this dosage range may provide the ideal balance between efficacy and toxicity. Most premature discontinuations due to side effects were because of gastrointestinal intolerance and an unacceptable increase in serum creati-

33

nine level, in most studies defined as an increase of 50% of its initial value. The use of a 50% elevation in serum creatinine level, as stated by Tugwell et a1,46may be too liberal with regard to tubular hypersecretion of creatinine because progressive glomerular disease may be concealed.50 Others argue that if serum creatinine concentrations increase more than 30% above baseline, the dose should be reduced.3 Patients with RA are more susceptible to cyclosporineinduced renal damage than patients with other autoimmune diseases49,51; in contrast to the latter, in RA patients given high-dose (10 mg/ kg/d) cyclosporine the serum creatinine increase was only partially reversible.52-54 The experience gained in these trials was helpful in formulating protocols for later trials, resulting in better selection of patients, closer monitoring, and stricter guidelines to reduce the dose when specified limits were exceeded. Moreover, the early trials were performed in disabled patients with intractable RA; such patients may be more susceptible to more severe cyclosporine toxicity in view of their worse clinical condition and previous treatment with many potentially nephrotoxic antirheumatic drugs, eg, gold and D-penicillamine.55 Cyclosporine should not be given to patients with preexisting nephropathy@j and/or hypertension.45 The exquisite sensitivity of RA patients to the renal effects of cyclosporine probably is related to the concurrent use of NSAIDS.~~ A higher incidence of renal toxicity is reported in patients over 60 years old.45 Another risk factor for cyclosporine nephrotoxicity is a relatively high (90 umol/L or more) pretreatment serum creatinine concentration.45,53 However, it must be emphasized that the serum creatinine level is not a reliable marker of renal function in RA.56 Because serum creatinine is an insensitive indicator of creatinine clearance, even when formulae such as that proposed by Cocroft et a15’are used, collection of three 24-hour urine specimens is needed to obtain a satisfactory estimate of creatinine excretion. It should be emphasized that serum creatinine levels and creatinine clearance rates are not sensitive indices of glomerular injury and underestimate changes in the physiological glomerular filtration rate.50 Progressive glomerular disease may be concealed by tubular hypersecretion of creatinine; a 50%

34

DIJKMANS

reduction in the glomerular filtration rate is necessary before the serum creatinine level increases.58 Determinations of glomerular filtration rate and renal blood flow rate are required to provide a more accurate measurement of renal function during cyclosporine therapy.50 No correlation was found between increase in serum creatinine level during cyclosporine therapy and blood levels of the drug.53 In contrast with our study using a maximum of 10 mg/kg, cyclosporine nephrotoxicity was reversible after administration of 5 mg/kg over 24 weeks.59 However, continuation of similar cyclosporine doses for a mean of 21 months resulted in serum creatinine values that did not return to pretreatment values.48 CYCLOSPORINE

IN THE

1990s

From the studies of the 1980s we have learned that cyclosporine is an effective but toxic drug in RA. It might be worthwhile to administer cyclosporine much earlier in the course of the disease, in as much as it exerts maximum activity at the moment of antigen presentation.‘jO Although that moment is not known in RA, earlier cyclosporine administration might prove more effective, as it is in type II collagen-induced arthritis in animals.61 Another reason to treat RA patients with cyclosporine early is that subclinical renal dysfunction is frequent in patients with long-standing disease, a result of chronic drug therapy and possibly the disease process itselp$ therefore, patients with a shorter disease duration and shorter time of exposure to nephrotoxic drugs might be less sensitive to cyclosporine nephrotoxicity. Nephrotoxicity is manageable but not negligible. The exquisite sensitivity of RA patients to the renal effects of cyclosporine appears, among others effects, related to the concurrent use of NSAIDs. The acute depressant effect of cyclosporine on renal function is related to a change in the balance of vasodilatory to vasoconstrictive intrarenal prostaglandins in favor of the latter, causing a dose-dependent reduction in renal blood flo~.~~ The additional inhibition of prostaglandin synthesis by NSAIDs probably works in concert with the effect of cyclosporine to depress renal function further. Because withdrawal of NSAIDs is not feasible in most RA patients, other means must be sought to address this problem such as coadministration of long-acting prostaglandin

ET AL

analogues or fish oil. Preliminary and experimental data and results in renal transplant recipients indicate that cyclosporine nephrotoxicity might be reduced by these agents.63-66 Renal tubular effects of cyclosporine occur independently of the reduced glomerular rate.67 Defects of the proximal tubule, primarily the third segment, cause impaired secretion of urea and uric acid and reduced fractional excretion of sodium, lithium, potassium, and phosphate, as well as reduced bicarbonate reabsorption, hyperchloremia, and metabolic acidosis.2 The effect on the distal tubule potentiates the hyperkalemia induced in the proximal tubule.2 Concerning the handling of creatinine, progressive glomerular disease may be concealed by tubular hypersecretion of creatinine.50 Apart from these possibilities, a dosage schedule that can optimize efficacy and safety in the individual patient is needed. One possibility is to lower the initial daily dose of cyclosporine. The highest initial daily dose needed may be only 2.5 mg/kg, and increasing the dose must follow the principle “go low, go s10w.“~~Guidelines for reducing the dose should be a decrease in renal function or an increase in blood pressure, not cyclosporine blood levels. If serum creatinine concentrations increase more than 30% above baseline, the dose should be reduced.3 However, increase in serum creatinine level is a crude parameter of detoriation of renal function; the latter is reflected more accurately by decreases in measured creatinine clearance, glomerular filtration rate, and renal blood flow rate.50 In view of the problems associated with the interpretation of serum creatinine level, the creatinine clearance should be measured at baseline as a minimum requirement in future trials. For inclusion in these trials, the patient’s creatinine clearance should not to be less, arbitrarily, than 80 mlimin. Because impaired renal function is a risk factor for cyclosporine creatinine nephrotoxicity,45,53 a pretreatment clearance of at least 80 mL/min seems safe. No definite judgment can be given about the duration of cyclosporine administration; 6 months or even 1 year duration seems safe under strict monitoring; after a longer administration, nephrotoxicity may not be reversible. As a guideline, a 15% loss of renal function, if stable, might be

CYCLOSPORINE

35

IN RA

an acceptable price to pay for the prolonged administration of cyclosporine. At present we are conducting a double-blind trial comparing chloroquine and cyclosporineunder the conditions described above-in patients with early arthritis. The preliminary data indicate less nephrotoxicity than in earlier trials. The results of this and other studies will

determine what place cyclosporine will have in the order of antirheumatic drugs. ACKNOWLEDGMENT The authors are greatly indebted to Professor Dr F.C. Breedveld and Dr R.B.M. Landewe for their critical reading of the manuscript, to Dr J.D. Macfarlane for correcting the English, and to J. Ravensbergen for typing the manuscript.

REFERENCES 1. Bore1 JF: Comparative study of in vitro and in vivo drug effects on cell mediated cytotoxicity. Immunology 31:631-641,1988 2. Kahan BD: Drug therapy: Cyclosporine. N Engl J Med 321:1725-1738,1988 3. Thomson AW, Neild GH: Cyclosporine: Use outside transplantation. Br Med J 302:4-5,199l 4. Cockfield SM, Halloran PH. Cyclosporine: A new decade. Annals RCPSC 24:25-g, 1991 5. Kimball PM, Kerman RH, Kahan BD: Failure of prolyl-peptidyl isomerase to mediate cyclosporine suppression of intracellular activation signal generation. Transplantation 51:509-513,199l 6. Kimball PM, Kerman RH, Kahan BD: Production of synergistic but nonidentical mechanisms of immunosuppression by rapamycin and cyclosporine. Transplantation 51:486490,199l 7. Hess AD, Tutschka PJ, Santos GW: Effects of cyclosporin A on human lymphocyte responses in vitro. III. CsA inhibits the production of T lymphocyte growth factors in secundary mixed lymphocyte responses but does not inhibit the response of primed lymphocytes to TCGF. J Immunol 128:355-359, 1982 8. Elliot JF, Lin Y, Mizel SB, et al: Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science 226:1439-1441,1984 9. Kronke M, Leonard WJ, Depper JM, et al: Cyclosporine A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Nat1 Acad Sci USA 81:5214-5218,1984 10. RytIel B, Gotz U, Heuberger B: Cyclosporin receptors on human lymphocytes. J Immunol129:1978-1982,1982 11. Metcalfe S: Cyclosporine does not prevent cytoplasmic calcium changes associated with lymphocyte activation. Transplantation 38:161-164, 1984 12. Manger B, Hardy KJ, Weiss A, et al: Differential effect of cyclosporin A on activation signaling in human T cell lines. J Clin Invest 77:1501-1506,1986 13. Colombani PM, Robb A, Hess AD: Cyclosporin A binding to calmodulin: A possible site of action on T lymphocytes. Science 228:337-339,1985 14. LeGrue SJ, Turner R, Weisbrodt N, et al: Does the binding of cyclosporine to calmodulin result in immunosuppression? Science 234:68-71,1986 15. Maniatis T, Goodbourn S, Fischer JA: Regulation of inducible and tissue-specific gene expression. Science 236: 1237-1244,1987 16. Miyawaki T, Yachie A, Ohzeki S, et al: Cyclosporin A does not prevent expression of Tat antigen a probable TCGF receptor molecule, on mitogen-stimulated human T cells. J Immunol130:2737-2742, 1983

17. Kupiec-Weglinski JW, Filho MA, Strom TB, et al: Sparing of suppressor cells: A critical action of cyclosporine. Transplantation 38:97-101, 1984 18. Wang BS, Heacock EH, Chang-Xue Z, et al: Evidence for the presence of suppressor T lymphocytes in animals treated with cyclosporin A. J Immunol 128:13821385,1982 19. Harris ED Jr: Mechanisms of disease: Rheumatoid arthritis-Pathophysiology and implications for therapy. N Engl J Med 322:1277-1289,199O 20. Trentham DE: Immunoresponse to collagen, in Gupta S, Talal N (eds): Immunology of Rheumatic diseases. New York, NY, Plenum, 1985, pp 301-323 21. Holoshitz J, Naparstek Y, Ben-Nun A, et al: Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science 21956-58, 1983 22. Zvaifler NJ, Silver RM: Cellular immune events in the joints of patients with rheumatoid arthritis, in Gupta S, Talal N (eds): Immunology of Rheumatic Diseases. New York, NY, Plenum, 1985, pp 517-542 23. Talal N: Cyclosporine as an immunosuppressive agent for autoimmune diseases: Theoretical concepts and therapeutic strategies, in Kahan BD: Cyclosporine. Applications in Autoimmune Diseases. Philadelphia, PA, Grune & Stratton, 1988, pp 11-15 24. Pitzalis C, Kingsley G, Murphy J, et al: Abnormal distribution of the helper-inducer and suppressor-induced T-lymphocyte subsets in the rheumatoid joint. Clin Immuno1 Immunopathol45:252-258, 1987 25. Lasky HP, Bauer K, Pope RM: Increased helper inducer and decreased suppressor inducer phenotypes in the rheumatoid joint. Arthritis Rheum 31:52-59,1988 26. Pitzalis C, Kingsley G, Lanchbury JSS, et al: Expression of HLA-DR, DQ and DP antigens and interleukin-2 receptor on synovial fluid T lymphocyte subsets in rheumatoid arthritis: Evidence for “frustrated” activation. J Rheumatol 14:662-666, 1987 27. Thomson AW, Whiting PH, Simpson JG: Cyclosporine: Immunology, toxixity and pharmacology in experimental animals. Agents Actions 15:306-327,1984 28. Nussenblatt RB, Palestine AG, Chan CC: Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am J Ophtalmol96:275-282,1983 29. Miescher PA, Favre H, Mihatsch MJ, et al: The place of cyclosporine A in the treatment of connective tissue diseases. In: Kahan BD. Cyclosporine. Applications in autoimmune diseases. Philadelphia, PA, Grune & Stratton, 1988, pp 224-237 30. Ellis CN, Gorsulowsky DC, Hamilton TA, et al:

36

Cyclosporine improves psoriasis in a double-blind study. JAMA256:3110-3116,1986 31. Feutren G, Papoz L, Assan R, et al: Cyclosporin increases the rate and length of remissions in insulindependent diabetes of recent onset: Results of a multicentre double-blind trial. Lancet 2:119-124,1986 32. Bougneres PF, Care1 JC, Castano L, et al: Factors associated with early remission in type I diabetes in children treated with cyclosporine. N Engl J Med 318:663-670, 1988 33. Tejani A, Butt K, Khawar MR, et al: Cyclosporine (CY) induced remission of relapsing nephrotic syndrome (RNS) in children. Kidney Int 29:206,1986 (abstr) 34. Wiesner RH, Ludwig J, Lindor KD, et al: A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 322:1419-1424, 1990 35. Tindall RSA, Rollins JA, Phillips JT, et al: Prehminary results of a double-blind, randomized, placebocontrolled trial of cyclosporine in myasthenia gravis. N Engl J Med 316:719-724,1987 36. Hyams JS, Ballow M, Leichter AM: Cyclosporine treatment of auto-immune chronic active hepatitis. Gastroenterology 3:890-893, 1987 37. Herrmann B, Miiller W: Die Therapie der chronisthen Polyarthritis mit Cyclosporin A, einem neuen Immunosuppressivum. Aktuel Rheumatol4:173-186,1979 38. Rijthoven AWAM van, Dijkmans BAC, Goei The HS, et al: Cyclosporin treatment for rheumatoid arthritis: A placebo-controlled double-blind multicentre study. Ann Rheum Dis 45:726-731,1986 39. Weinblatt ME, Coblyn JS, Fraser PA, et al: Cyclosporin A treatment of refractory rheumatoid arthritis. Arthritis Rheum 30:11-17, 1987 40. Forre 0, Bjerkhoel F, Salvesen CF, et al: An open, controlled, randomized comparison of cyclosporin and azathioprine in the treatment of rheumatoid arthritis: A preliminary report. Arthritis Rheum 30:88-92,1987 41. Tugwell P, Bombardier C, Gent M, et al: Low dose cyclosporine in rheumatoid arthritis: A pilot study. J Rheumatol14:1108-1114, 1987 42. Dougados M, Amor B: Cyclosporin A in rheumatoid arthritis: Preliminary clinical results of an open trial. Arthritis Rheum 30:83-87,1987 43. Dougados M, Awada H, Amor B: Cyclosporine in rheumatoid arthritis: a double-blind, placebo controlled study in 52 patients. Ann Rheum Dis 47:127-133,1988 44. Yocum DE, Khpper JH, Wilder RL, et al: Cyclosporin A in severe, treatment-refractory rheumatoid arthritis. Ann Intern Med 109:863-869,1988 45. Dougados M, Luchesne L, Awada H, et al: Assessment of efficacy and acceptability of low dose cyclosporin in patients with rheumatoid arthritis. Ann Rheum Dis 48:550556,1989 46. Tugwell P, Bombardier C, Gent M, et al: Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 335:1051-1055,199O 47. Rijthoven AWAM van, Dijkmans BAC, Goei The HS, et al: Comparison of cyclosporine and d-penicillamine for rheumatoid arthritis: A randomized double-blind study. J Rheumatol18:815-820,199l 48. Rijthoven AWAM van, Dijkmans BAC, Goei The HS, et al: Long term cyclosporine therapy in rheumatoid arthritis. J RheumatoI18:19-23,199l 49. Palestine AR, Nussenblatt RB, Chan C-C: Side

DIJKMANS

ET AL

effects of systemic cyclosporine in patients not undergoing transplantation. Am J Med 77:652-656,1984 50. Weinblatt M, Helfgott S, Coblyn J, et al: The effects of cyclosporin A on eicosanoid excretion in patients with rheumatoid arthritis. Arthritis Rheum 34:481-485, 1991 51. Ludwin D, Bennett KJ, Grace AM, et al: Nephrotoxicity in patients with rheumatoid arthritis treated with cyclosporine. Transplant Proc 20:367-370, 1988 (suppl4) 52. Berg KJ, Forre 0, Bjerkhoel F, et al: Side effects of cyclosporin A treatment in patients with rheumatoid arthritis. Kidney Int 29:1180-1187,1986 53. Dijkmans BAC, Rijthoven AWAM van, Goei The HS, et al: Effect of cyclosporine on serum creatinine in patients with rheumatoid arthritis. Eur J Clin Pharmacol 31:541-545,1987 54. Boers M, Rijthoven AWAM van, Goei The HS, et al: Serum creatinine levels two years later: follow-up of a placebo-controlled trial of cyclosporine in rheumatoid patients. Transplant Proc 20:371-375,1988 (suppl4) 55. Boers M, Dijkmans BAC, Breedveld FC, et al: Subclinical renal dysfunction in rheumatoid arthritis. Arthritis Rheum 33:95-101, 1990 56. Boers M, Dijkmans BAC, Breedveld FC, et al: Errors in the prediction in creatinine clearance in patients with rheumatoid arthritis. Br J Rheumatol27:233-235,1988 57. Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41,1976 58. Ross EA, Wilkinson A, Hawkins RA, et al: The plasma creatinine concentration is not an accurate reflection of the glomerular filtration rate in stable renal transplant patients receiving cyclosporine. Am J Kidney Dis 10:113-117,1987 59. Boers M, Dijkmans BAC, Rijthoven AWAM van, et al: Reversible nephrotoxicity of cyclosporine in rheumatoid arthritis. J Rheumatol17:38-42, 1990 60. Green CJ: Experimental transplantation. Prog Allergy 38:123-158,1986 61. Henderson B, Staines NA, Burrai I, et al: The anti-arthritic and immunosuppressive effects of cyclosporine on arthritis induced in the rat by type II collagen. Clin Exp Immunol57:51-56,1984 62. Kahan BD: Cyclosporin nephrotoxicity: Pathogenesis, prophylaxis, therapy, and prognosis. Am J Kidney Dis 8:323-331, 1986 63. Elzinga L, Kelley VE, Houghton DG, et al: Modification of experimental nephrotoxicity with fish oil as the vehicle for cyclosporine. Transplantation 43:271-274,1987 64. Paller M: The prostaglandin EI, analog misoprostol reverses acute cyclosporine nephrotoxicity. Transplant Proc 20:634-637,1988 (suppl3) 65. Homan van der Heide JJ, Bilo HJG, Tegzess AM, et al: Omega-3 polyunsaturated fatty acids improve renal function in renal transplant recipients treated with cyclosporin-A. Kidney Int 35:516,1989 (abstr) 66. Moran M, Mozes MF, Maddox MS, et al: Prevention of acute graft rejection by the prostaglandin El analogue misoprostol in renal transplant recipients treated with cyclosporine and prednisone. N Engl J Med 322:1183-1188, 1990 67. Weinberg JM: Issues in the pathophysiology of nephrotoxic renal tubular cell injury pertinent to understanding cyclosporine nephrotoxicity. Transplant Proc 17:81-90,1985 (SUPPI)

Cyclosporine in rheumatoid arthritis.

The efficacy and toxicity of cyclosporine in the treatment of patients with rheumatoid arthritis (RA) are reviewed. Most of the early trials were rest...
789KB Sizes 0 Downloads 0 Views