Cyclosporin and tacrolimus: their use in a routine clinical setting for scleroderma

S. J. Morton and R. J. Powell

Clinical Immunology Unit, University Hospital, Nottingham, UK


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Background. Cyclosporin and tacrolimus are immunomodulatory drugs which act predominantly on T cells. Improvements in certain manifestations, particularly skin tightness, have been observed in a number of patients with scleroderma treated with these drugs. However, to date there have been no reports of their use in a routine clinical setting.

Methods. Patients attending clinical immunology clinics who had progressive systemic sclerosis and related syndromes and who had received cyclosporin and/or tacrolimus were identified. Details of their treatment, including drug dosage, duration of and response to treatment, side-effects and reasons for withdrawal, were recorded.

Results. Sixteen patients had been given cyclosporin and 13 of these had been treated for skin tightness. Half noticed significant softening of their skin whilst on treatment, and resolution was observed in all four of the patients treated for digital vasculitis. Side-effects were common and dose-limiting, and contributed to withdrawal in 12 out of 13 patients. Eight patients had been treated with tacrolimus; two of these had stopped the drug because of progression of their disease, one developed diarrhoea, prompting withdrawal, one stopped tacrolimus following improvement, and four remained on the drug. Side-effects had occurred in three patients.

Conclusion. Improvements in skin occur in approximately half of all cases of scleroderma treated with either cyclosporin or tacrolimus, suggesting a beneficial effect. Side-effects, especially hypertension, are common with cyclosporin and often necessitate withdrawal. Adverse effects are also observed with tacrolimus, but in the small cohort so far treated only one patient had stopped the drug for this reason.

KEY WORDS: Scleroderma, Cyclosporin, Tacrolimus, Skin tightness, Side-effects


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
The response of patients with graft-vs-host disease to treatment with the immunomodulatory drug cyclosporin [1] stimulated interest in the possible benefits to scleroderma patients of treatment with such drugs. Graft-vs-host disease and scleroderma share clinical and pathological characteristics, which are thought to be driven by T cells [2, 3]. In a study of systemic sclerosis patients by Roumm et al. [4], the degree of mononuclear cell infiltration in skin correlated with both the degree and the progression of skin thickening [4]. Individual case reports and early studies of cyclosporin for scleroderma have yielded promising results [511]. Furthermore, the skin softening that has been observed in several patients on treatment has been matched in some by changes in the ratio of collagen types, specifically relative reductions in the quantity of immature collagen (type III) [8]. The effects on internal organ manifestations of scleroderma have been less convincing. The aim of this study was to examine the value of cyclosporin, and the allied drug tacrolimus, in a routine clinical setting.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
All patients with progressive systemic sclerosis or a related syndrome, attending clinical immunology clinics in Nottingham who had received cyclosporin and/or tacrolimus were identified. Details of their disease, including its duration and specific clinical features, were extracted from medical notes. Echocardiograms, lung function tests/CT scans and studies of gastrointestinal function were not carried out routinely in this cohort of patients, and therefore the effects of cyclosporin and/or tacrolimus on the heart, lung and gastrointestinal tract were not studied. The following information relating to their treatment with cyclosporin and tacrolimus was obtained: dates of starting, and if relevant, stopping cyclosporin or tacrolimus; cyclosporin/tacrolimus dose; starting dose, maximum dose and mean dose; adjunctive use of steroids as part of a complete drug history; precise indication of treatment; level of disease activity at the start of treatment; partial remission or active; response to treatment; side-effects; and reasons for withdrawal.

Both cyclosporin and tacrolimus were given daily in two divided doses. Trough levels were measured monthly and the drug dose was adjusted to maintain a blood level between 95 and 205 ng/ml for cyclosporin and 1.5–15 µg/l for tacrolimus.

The response to treatment, as judged from the case notes, was classified as follows: good response =clinically apparent, marked improvement in a symptom/sign during treatment; slight improvement =definite, but not marked improvement in a symptom/sign; unchanged = no perceived improvement or deterioration at any stage during treatment; worsened = never any improvement, deteriorated from the outset.

In the majority of cases the response to treatment was based upon a combination of the patient's opinion and the physician's general assessment rather than on objective measures of disease activity, such as skin scores.

For the subgroup of patients who were considered to be in partial remission at the start of treatment, response was classified more simply as ‘progression’ or ‘no progression’.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Cyclosporin for scleroderma
Eight patients with diffuse cutaneous systemic sclerosis, one patient with limited cutaneous disease, four patients with the CREST (calcinosis, Raynaud's phenomenon, oesophageal involvement, sclerodactyly, telangectasia) syndrome, two patients with scleroderma overlap syndromes [one with scleroderma/polymyositis and one with systemic lupus erythematosus (SLE)/scleroderma] and one patient with morphoea (total = 16 patients) had been treated with cyclosporin between April 1997 and February 1999. All patients with systemic disease satisfied the American Rheumatism Association preliminary criteria for the classification of systemic sclerosis [13].

Thirteen patients were females and three were males, and their mean age at the time of initiation of treatment with cyclosporin was 42.3 yr (range 12–62 yr). The average duration of disease was 8.1 yr (range 1–27 yr), and 14 of the 16 patients had received one or more immunosuppressant/modulator drugs prior to initiation of cyclosporin treatment (Table 1Go). The indications for treatment were skin tightness, morphoea, digital vasculitis, fatigue, arthralgia, swollen fingers and dysphagia.


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TABLE 1. Demographic features and details of response to cyclosporin and tacrolimus

 
Cyclosporin was initiated at a mean daily dose of 3.4 mg/kg (range 2.4–4.1 mg/kg). Over the entire treatment period the mean daily dose was 3.7 mg/kg (range 2.3–5.6 mg/kg), and the maximum daily dose ranged from 2.7 to 6.9 mg/kg (mean 4.5 mg/kg). The average trough concentration of cyclosporin was 103 µg^sol;ml (53–186 µg/ml).

Only one patient took prednisolone whilst on cyclosporin; the dose was tapered from 5 mg and stopped altogether 56 days into the treatment period. Six of 16 patients were taking an H2 blocker or a proton pump inhibitor; in the patients with pre-existing and/or new hypertension the drugs used included angiotensin converting enzyme (ACE) inhibitors, calcium antagonists and diuretics, either alone or in combination.

Response to treatment.
Marked improvement in skin tightness, classified as a good response, occurred in half of the patients treated for this indication. Resolution of digital infarcts and prevention of further infarcts occurred in all four patients with this manifestation (Table 1Go).

Side-effects.
Fourteen of the 16 patients developed side-effects whilst on cyclosporin, the details of which are described in Table 2Go. For the purpose of this study, hypertension was defined as a blood pressure which was considered sufficiently high (usually >90 mmHg diastolic) to warrant treatment with antihypertensive drugs. Renal toxicity was defined as a rise in serum creatinine of >30% above baseline values.


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TABLE 2. Adverse effects and reasons for withdrawal of tacrolimus and cyclosporin

 

Duration of treatment and reasons for withdrawal.
Three of the 16 patients were still taking cyclosporin at the time of the audit; they had been receiving the drug for 35, 528 and 383 days, respectively. The remaining 13 patients had stopped cyclosporin, and of these 12 had stopped because of side-effects, lack of apparent benefit or a flare of disease activity after initial improvement whilst on the drug. A single patient had stopped cyclosporin because she was considered to have gained maximal benefit from the drug and there was no clinical progression of her disease. The 13 patients who were no longer taking cyclosporin had received it for an average duration of 244 days, i.e. approximately 8 months (range 13–672 days).

Tacrolimus for scleroderma
A total of eight patients had been started on tacrolimus for scleroderma or allied overlap syndromes (four with scleroderma, two with CREST, one with an SLE/scleroderma overlap syndrome and one with a scleroderma/polymyositis overlap syndrome). In every case the tacrolimus was initiated in patients who had not responded adequately or who had developed side-effects while on cyclosporin (Table 1Go).

The dosage regimen for tacrolimus was as follows: mean starting dose 0.04 mg/kg daily (range 0.03–0.06 mg/kg daily); average mean daily dose 0.07 mg/kg (range 0.03–0.1 mg/kg); mean maximum daily dose 0.1 mg/kg (range 0.03–0.18 mg/kg). The average tacrolimus trough concentration was 4.7 µg/l (range 1.75–9.5 µg/l).

None of the patients was on steroids whilst taking tacrolimus. Five patients were on an H2 blocker or a proton-pump inhibitor, four were taking antihypertensive medication and two were receiving hormone replacement therapy.

The indications for, response to, and duration of treatment with tacrolimus in individual patients are shown in Table 1Go.

Side-effects.
Three patients reported side-effects (Table 2Go): mild headaches, diarrhoea, and tremor and paraesthesia. Four of the patients had pre-existing hypertension, and although it was necessary to continue with their antihypertensive medication, no further rises in blood pressure were seen while the patients were on tacrolimus. Significant rises in serum creatinine had not been observed.

Duration of treatment and reasons for withdrawal.
Four patients had been forced to stop tacrolimus at 21, 65, 209 and 236 days, respectively. The average duration of treatment in the remaining four patients who were continuing on the drug was 209 days, i.e. approximately 7 months (range 33–448 days). In three of the four patients who were no longer taking tacrolimus, the reason for withdrawal was failure to control disease; in the fourth case it was stopped because of drug-induced diarrhoea. Two patients had since started pulse i.v. cyclosphosphamide and were responding well; the other two had persisting problems with recurrent superficial thrombophlebitis and leg ulceration.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
In this, the first retrospective audit of the use of cyclosporin and tacrolimus in a routine clinical setting, we have shown that a proportion of patients with skin tightness secondary to progressive systemic sclerosis and related syndromes improve whilst on these drugs. Cyclosporin, however, is poorly tolerated by many patients, and withdrawal is often necessary.

The drawbacks of the study relate to its retrospective design, which precludes the assessment of response according to a validated scoring system. In addition, not all patients had been thoroughly characterized in terms of heart, lung, kidney and gastrointestinal involvement, and it was therefore not possible to assess accurately the effects of cyclosporin and tacrolimus on these systems. We were, however, able to gain an overall impression of the usefulness of these drugs when used routinely, outside the context of prospective trials with their strict entry criteria.

The changes observed in patients on cyclosporin were mixed. Skin tightness was the most common complaint treated, and only half of the patients with this manifestation noticed a significant improvement. Furthermore, in the absence of a control group, the contribution of cyclosporin to the improvements observed cannot be ascertained. If it is assumed that the improvements were a direct result of the use of cyclosporin, the rates of success reported here are similar to those reported by Zachariae et al. [10], who, as in our study, treated patients with disease durations ranging between 1 and 30 years. This contrasts with most other studies, in which a higher proportion of patients noticed skin softening whilst on cyclosporin but disease duration was relatively short [8, 11, 12]. An alternative explanation for the relatively low success rate could be the diagnostic heterogeneity of our patient group: a mixture of pure systemic sclerosis, CREST, morphoea and scleroderma overlap syndromes. In addition, the response has been assessed differently by the various authors; in our study it was based upon a general assessment by the treating physician; Clements et al. [12], on the other hand, relied upon skin scores, classing as a good response a decrease in skin score of >35%.

Unfortunately, much of the apparent benefit realized by patients on cyclosporin was counterbalanced by side-effects. Fourteen of the 16 patients developed one or more side-effects whilst on the drug, of which hypertension was the most common (eight patients). Furthermore, side-effects with or without lack of efficacy prompted withdrawal of cyclosporin in 12 of 13 patients. Only one patient came off cyclosporin because her disease was considered to be well controlled. Most other studies [8, 1012, 14] have reported similarly high frequencies of side-effects, but only a minority of these effects were of sufficient severity to warrant drug withdrawal. It may be that the availability of tacrolimus has lowered our threshold for stopping cyclosporin when side-effects occur. It is also possible that the exclusion criteria employed in previous prospective studies, for example, raised blood pressure and decreased creatinine clearance, reduced the risk of side-effects such as hypertension and renal toxicity.

Our experience of tacrolimus is similar. Four of the eight patients who have been started on treatment continue on it. Two of these had overtly active disease at the outset, and skin softening and improvement in arthralgia/stiffness occurred in both. In the other two patients still on tacrolimus, treatment was commenced to prevent progression of disease (after developing side-effects on cyclosporin), and both of these patients remain well. Of the four patients who are no longer taking tacrolimus, three stopped it because of inadequate control of their disease. Only one patient came off the drug because of troublesome drug-associated diarrhoea. There has been one other study of tacrolimus in scleroderma, published in abstract form [15], but the patient cohort was not comparable with our own in that they all had severe, rapidly progressive disease of short duration. The high rate of mortality (four of 10 patients) and the high relapse rate in initial responders probably reflect the severity of their disease.


    Conclusion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Approximately half of all patients with scleroderma and related syndromes treated for skin tightness noticed skin softening whilst on cyclosporin (3.7 mg/kg daily) or tacrolimus (0.07 mg/kg daily). The exact contribution of the two drugs to the observed changes is not known, and future case–control studies would help to clarify the matter. Both drugs have side effects that occur commonly, hypertension occurring in half of all patients treated, and with cyclosporin they are often dose-limiting.


    Notes
 
Correspondence to: R. J. Powell, Clinical Immunology Unit, University Hospital, Nottingham NG7 2UH, UK. Back


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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Submitted 23 June 1999; revised version accepted 28 January 2000.



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