Clinical Immunology Unit, University Hospital, Nottingham, UK
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Abstract |
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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
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Introduction |
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Methods |
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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 1.515 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.
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Results |
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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 1262 yr). The average duration of disease was 8.1 yr (range 127 yr), and 14 of the 16 patients had received one or more immunosuppressant/modulator drugs prior to initiation of cyclosporin treatment (Table 1). The indications for treatment were skin tightness, morphoea, digital vasculitis, fatigue, arthralgia, swollen fingers and dysphagia.
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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 1).
Side-effects.
Fourteen of the 16 patients developed side-effects whilst on cyclosporin, the details of which are described in Table 2. 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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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 13672 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 1).
The dosage regimen for tacrolimus was as follows: mean starting dose 0.04 mg/kg daily (range 0.030.06 mg/kg daily); average mean daily dose 0.07 mg/kg (range 0.030.1 mg/kg); mean maximum daily dose 0.1 mg/kg (range 0.030.18 mg/kg). The average tacrolimus trough concentration was 4.7 µg/l (range 1.759.5 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 1.
Side-effects.
Three patients reported side-effects (Table 2): 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 33448 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.
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Discussion |
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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.
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Conclusion |
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Notes |
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References |
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