Departments of Paediatrics and Medicine, University of Toronto and the Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
Correspondence to:
R. M. Laxer, Department of Paediatrics and Medicine, University of Toronto and the Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
Therapy of patients with chronic disease may have serious consequences years after the treatment has been administered. This article will address medications used in children and adolescents with rheumatic disease that have short-term toxicity with long-term implications, as well as medications that may not have short-term toxicity but have potential long-term risks, and will focus on the medications that are currently in common use for patients with rheumatic disease. It is extremely difficult to ascertain the long-term risks for many reasons (Table 1), particularly small numbers of patients treated and closely followed for a prolonged period of time, resulting in an inability to determine true risks. Only careful, long-term follow-up studies with large cohorts of well-categorized patients will provide some insight into these risks.
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Corticosteroid therapy
Systemic corticosteroids are used in virtually all the rheumatic diseases, and the short-term toxicities are well known. Many of these short-term toxicities may have long-term effects.
Growth suppression is common, particularly if growth is impaired around the time of puberty; in fact, it is at this developmental stage that children are especially susceptible to growth suppression from corticosteroids. While the effects of corticosteroids on final height are difficult to distinguish from the natural history of the underlying disease for which they are being used, daily oral prednisone therapy for >18 months has been associated with diminished final height [1]. In addition to the reduction of final height, the long-term psychological effects of short stature can be significant.
Similarly, the psychological effects of the increased weight gain and changes in body image frequently induced by corticosteroids must be closely attended to. Children who develop severe cushingoid features with moon faces and marked weight gain are subject to insults by their peer group. Although the long-term psychological and behavioural consequences of this altered body image have not been well studied, it is quite possible that the short-term impact will have long-term effects as to how these patients will view themselves and interact with their peer group in the future.
The use of high doses of corticosteroid also has many effects on bone. Only recently have studies on bone density in children with rheumatic disease been carried out in a systematic fashion. These show that children with arthritis are at significant risk of osteoporosis for many reasons, including poor dietary intake, inactivity and the effects of cytokines on osteoclast activation. A major risk factor leading to osteoporosis is corticosteroid therapy. When severe, vertebral fractures may occur and lead to loss of ultimate height. There is also a theoretical (not proven) possibility that ultimate peak bone mass will not be achieved, as has been noted in adolescents with anorexia nervosa [2].
Avascular necrosis of bone is another risk factor of corticosteroid therapy, and occurs in 15% of patients with systemic lupus erythematosus (SLE). Significant long-term consequences of bone ischaemia are collapse and subsequent degenerative arthritis, which may require joint replacement, with its many attendant complications.
Recently, patients with SLE have been documented to have `new' morbidity, as a result of advances in treatment. Of significant concern is premature atherosclerosis, an important factor responsible for the late morbidity and mortality of patients with SLE. An important contributor to the development of atherosclerotic heart disease is corticosteroid therapy. The hyperlipidaemia associated with both underlying disease and corticosteroid therapy probably predisposes to the premature development of this arterial disease [3].
Finally, the systemic use of corticosteroid has potential long-term ocular complications. Posterior subcapsular cataracts are related to the dose and duration of therapy. If detected early and the dose of steroid is reduced, there is little in the way of long-term visual complications. However, persistent use and extension of the cataracts will require ultimate operative corrective surgery. In addition, glaucoma is a known long-term ocular consequence of systemic corticosteroid therapy.
Topical use of corticosteroid therapy is common in children with juvenile rheumatoid arthritis (JRA). Ocular corticosteroids are the first-line treatments for the control of the uveitis of JRA. Unfortunately, the large doses frequently required to control severe cases of uveitis lead to local ocular complications with long-term consequences, i.e. cataracts and glaucoma.
Intra-articular corticosteroid therapy is used early and often in children with JRA. Cutaneous atrophy secondary to leakage of corticosteroid may result in a `nuisance' long-term consequence of local therapy. Skin breakdown may occur easily in these areas, especially if they are over pressure points. Radiological deposits of calcium occur frequently, and are seen more commonly in the smaller than the large joints. The long-term frequency and impact of this on joint function are unknown.
Methotrexate
Methotrexate, introduced for the treatment of childhood leukaemia in the 1940s, has become a mainstay of the treatment of JRA, and with more experience and comfort with its use, has been used much earlier in the treatment course. In addition, it is frequently introduced early in the treatment of juvenile dermatomyositis (JDM), scleroderma (especially localized), SLE and some vasculitides. At the doses used in the rheumatic diseases, it appears to be more anti-inflammatory than immunosuppressive.
The major initial concerns about long-term risk dealt with hepatic fibrosis. Extrapolating data from adult series suggests that, while caution is still necessary, cirrhotic liver disease, and even fibrosis, are both very uncommon. Suggested risk factors for hepatic fibrosis include female gender, obesity, increasing alcohol consumption and raised hepatic transaminases [4, 5]. Teenagers must be constantly reminded about the risks of alcohol consumption, as peer pressure so commonly leads these individuals to experiment with alcohol.
A potential, albeit uncommon, long-term risk is the development of methotrexate osteopathy. This has been reported in children with leukaemia who were treated with doses of 30 mg/m2 /week [6], as well as in adults with RA [7]. The clinical presentation is one of pain in the lower extremities resulting from stress fractures. As with corticosteroid, significant osteopenia at a critical age period may have long-term consequences on bone development.
It is important to remind adolescents treated with methotrexate that careful birth control must be practised if methotrexate is to be prescribed, and it is necessary to emphasize this frequently to patients. Recently, a case of methotrexate embryopathy was reported in a 20 year old with a 5 year history of JRA. Fetal exposure to methotrexate was estimated to be ~100 mg [8].
Finally, an area of controversy regarding long-term consequences of methotrexate is the development of lymphoproliferative disease. It is not clear whether reports of this association are coincidental or, in fact, causative [9]. Evidence in support of causation includes its many similarities to post-transplant malignancy (believed to be due to immunosuppression). These tumours may occasionally regress when methotrexate is stopped. One case was recently described in a child with systemic-onset JRA [10].
Classic `anti-rheumatic' agents
Sulphasalazine
Recently, several reports have suggested that sulphasalazine is beneficial for polyarticular JRA and HLA B27-related disease. While short-term adverse events are common, long-term risks are rare, as witnessed by the excellent safety profile in patients with inflammatory bowel disease. Case reports have described persistent hypogammaglobulinaemia as a long-term risk.
Gold
Intramuscular gold is rarely used in the treatment of JRA, except in patients with rheumatoid factor-positive disease. Long-term consequences are unusual, as most of the toxicity is reversible upon discontinuation of gold.
Penicillamine
Penicillamine, previously used for the treatment of JRA, is now reserved for scleroderma. It may be associated with long-term risks of the development of autoimmune disease, including pemphigus, myasthenia, fibrosing alveolitis, glomerulonephritis, polymyositis and SLE.
Hydroxychloroquine
Hydroxychloroquine is an important agent used in the management of SLE, JDM and JRA. Retinopathy is a potential long-term risk, but is avoidable if the daily dose is maintained at or below 6.5 mg/kg/day.
Cyclosporin A
Cyclosporin A is an immunosuppressive agent which inhibits the release of interleukin-2 and the subsequent cytokine cascade. Its role in paediatric rheumatic therapy is still unclear, with case series showing positive benefits in systemic and polyarticular JRA, JDM and SLE. In adults, it is effective both alone, and in combination with methotrexate in RA.
As with systemic corticosteroid treatment, cyclosporin A results in undesirable cosmetic effects consisting of hypertrichosis and gum hypertrophy which lead to altered body image and potential long-term consequences.
The renal toxicity of cyclosporin is one of the major features limiting its use in rheumatic disease. Short-term decline in renal function and hypertension both occur frequently, but are generally reversible with dose reduction. Of more concern is the potential development of chronic renal disease which on biopsy consists of an arteriolopathy and tubular interstitial disease. A worrisome note is that the process can progress in the face of normal renal function.
Another long-term theoretical concern is the development of lymphoreticular malignancy. In transplant recipients, these malignancies are frequently associated with EpsteinBarr virus. In one review of 1000 adult patients treated with cyclosporin, 17 developed tumours [11]. Because the risk of malignancy is felt to be increased in RA regardless of treatment, the true risk cannot be extrapolated to children with JRA.
Azathioprine
Azathioprine, a purine analogue metabolized to 6-mercaptopurine, interferes with DNA synthesis. Its most frequent use in paediatric rheumatic diseases is with SLE, although it is occasionally used in JRA, systemic vasculitis and JDM. There is ongoing debate as to whether azathioprine is associated with an increased risk of malignancy in adults with RA [12]. In children with JRA, a large series recently published documented four malignancies in 129 patients treated, two patients had also received chlorambucil [13]. It is unclear whether malignancy in azathioprine-treated patients should be considered a long-term risk.
Alkylating agents
Cyclophosphamide
Cyclophosphamide is an alkylating agent that results in reduced numbers of B cells. It has been used much more frequently over the last decade in paediatric rheumatic diseases. Its documented efficacy in severe lupus nephritis and systemic vasculitis, and the ability to use high doses of cyclophosphamide i.v. (which has significantly reduced short-term toxicity), are some of the reasons for its increased use. However, major concerns remain regarding the long-term risks which have limited its use to severe disease manifestations with potentially fatal outcome.
A recent retrospective review examined menstrual abnormalities in adolescents given cyclophosphamide by either the oral or i.v. route and suggested that the total dose administered is the most important predictor of menstrual disturbance [14]. While the oral route was associated with more frequent abnormalities, patients treated orally also received a much greater total cyclophosphamide dose. Other studies in adults have also suggested that total dose was important, as well as older age at the start of treatment, in predicting the development of amenorrhoea [15, 16].
Similar concerns have arisen with the use of cyclophosphamide in Wegener's granulomatosis, where sustained amenorrhoea occurred in 57% of adults. The risk of malignancy, not yet addressed in the SLE population, is increased in patients with Wegener's granulomatosis treated with cyclophosphamide; bladder cancer and lymphoma are the two most common reported malignancies [17]. The paediatric experience is still very limited; the largest series did not report malignancy in 23 patients with a mean follow-up of 8.7 yr, but did document a 28% incidence of infertility [18].
In children with nephrotic syndrome or malignancy treated with daily oral cyclophosphamide, gonadal dysfunction in both males and females appears to be related to dose and also to the stage of pubertal development at the time of treatment, pre-pubertal children having a better outcome than those children who were already sexually mature [19].
Chlorambucil
Chlorambucil has similar mechanisms of action to cyclophosphamide. In paediatric rheumatology, it is generally reserved for amyloidosis, severe treatment-resistant uveitis, severe unresponsive systemic JRA and Behçet's disease with uveitis and/or encephalitis. Its indications are so narrow because of its severe long-term toxicity, which includes amenorrhoea, irreversible azoospermia (which occurred in 80% of males on long-term therapy for nephrotic syndrome in one series [20]) and malignancy, the risks of which increase with the dose administered. The most common malignancies are haematological, which occur in a range of 1.257.5% of JRA patients treated [21, 22].
Immunomodulation
The critical importance of long-term follow-up and determining risk is illustrated by data accumulated in a follow-up study of total lymphoid irradiation (TLI) in adult RA, in which 20 patients were randomized to receive TLI or a combination of cyclophosphamideazathioprine [23]. Nineteen of the 20 patients had 10 yr follow-up data available. Seven deaths occurred in the TLI group in the 10 yr follow-up period; importantly, five of the 10 deaths occurred beyond the fifth year, primarily related to malignancy or other B-cell proliferative disorders. These data emphasize a major problem with current studies, very few of which have followed patients beyond 5 yr.
Intravenous immunoglobulin therapy has been used sporadically in several rheumatic diseases with questionable efficacy. It continues to be used in some severe cases of systemic-onset JRA and in JDM. Long-term risks are both theoretical and practical. We and others have observed the development of renal disease and systemic vasculitis which required therapy [24, 25]. In addition, the potential risk of transmission of infectious agents can have long-term consequences.
Finally, a variety of `biologics' that target specific components of the immune system have been designed. Because they have only been used for the last few years, long-term data have not yet accumulated to allow the detection of long-term risk of this form of immunosuppression. However, the development of autoantibodies [with anti-tumour necrosis factor (TNF), soluble TNF receptor treatment] and persistent lymphopenia (with antibody to T-cell surface antigen treatment) are concerns with significant potential long-term consequences.
Summary
Although there are not many studies which have addressed long-term outcomes in children with rheumatic disease treated with immunosuppressive agents, the data that are available, as well as information from adult studies, suggest significant long-term concerns with all the agents that have demonstrable efficacy. This must lead us to investigate new methods of treatment which will not only be more effective, but also less toxic.
References