British Journal of Rheumatology 1992;31:635-641 REVIEW
IS THERE A DISEASE-MODIFYING DRUG FOR JUVENILE CHRONIC ARTHRITIS? BY M. ROONEY Molecular Rheumatology Section, MRC, Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ
PATHOGENESIS OF JUVENILE CHRONIC ARTHRITIS Since most of the adult therapies are aimed at depressing the synthesis of inflammatory mediators or immunosuppression, it is pertinent to examine the evidence for an immune reaction in JCA. To date JCA subgroups have been denned according to clinical rather than immunopathogenic differences and more recently immunogenetic studies have supported these divisions, suggesting a role for the immune response genes in JCA. Autoantibody production (ANA, rheumatoid factor (RF) and anti-lymphocytic antibodies) are present in various combination within the major subgroups [2-5], but are not unique to any one subgroup and are thus unlikely to be of aetiological significance (although we should not ignore their presence). A number of studies have explored lymphocyte phenotype and function in JCA with conflicting results. Normal and increased numbers of B cells have been found [2,6], although the B cell numbers in the study of Tsokos et al. [2] may have been an overestimation. Their observation that a significant population of these B cells were activated and exhibited suppressed responses to lectins and viral antigens is interesting. No consistent change in lymphocyte subsets has been observed. Some authors report normal CD4/8 ratios [7], whereas others report decreased ratios [8]. No consistent pattern has been observed with regard to disease subgroups or disease activity. However, Odum et al. [7] noted that there was an increase in the T cell population bearing late, but not early activation antigens suggesting chronic stimulation of this population of cells. Unfortunately they did not differentiate between the subpopulations of JCA. Barron et al. [9] found high levels of and T cell antibodies in the serum of almost all children with JCA irrespective of subgroup. Although there was only a slight and insignificant correlation between anti T cell antibody activity and disease activity, larger numbers of T cells reacted with JCA serum if they were activated first in vitro, suggesting that these antibodies were directed against activation antigens thus modulation the immune response. Again antigen and mitogen induced T cell responses have varied from study to study differences, perhaps being related to concomitant drug therapy [10-12]. One fairly consistent finding has been the presence of suppressor cytotoxic activity in JCA serum [9]. Whether this can be explained on the basis of anti T cell antibodies or immune complexes remains unclear [13]. © 1992 British Society for Rheumatology
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DISEASE-MODIFYING antirheumatic or second line drugs have been widely used in the treatment of juvenile chronic arthritis (JCA). The rationale for using these agents has been based on their efficacy in the treatment of adult rheumatic diseases. It is only in the last decade or so that we have re-classified the subgroups of JCA and research has shown quite clearly now that the immunopathology of childhood arthritis is somewhat different from that seen in adult disease. Juvenile chronic arthritis is divided into three major subgroups [1]. A fourth subgroup is gaining recognition in those with pauciarticular onset by a polyarticular course — extended pauci JCA. In approximately 40% of children the course of disease is polyarticular. In only 10% of cases are rheumatoid factors (RFs) detected when the disease closely resembles adult rheumatoid arthritis (RA) with a similar prevalence of the major histocompatibility antigen, HLA DR4 and an aggressive, erosive course. For the remaining 90%, the disease differs from adult RA. There is no association with HLA DR4. Erosions occur less frequently and joint ankylosis is more common. It is likely therefore that for the majority of children with polyarticular JCA the pathogenesis is different from that seen in adult RA. Thus it is probably inappropriate to assume that drugs which are effective in the latter will necessarily be useful in the former. Systemic JCA accounts for approximately 10% of the total population. Here again there are marked differences from adult RA. Rash and a characteristic high spiking fever are necessary for the diagnosis — very uncommon features in adult arthritides. Clinically significant visceral involvement is prominent in the former and usually absent in the latter. The sexes are affected equally in systemic JCA and, although some studies have reported an increased incidence of the HLA DR4 and Dw7 antigens, it has been disputed by others. An almost identical disease does occur but rarely in the adult population and it should be noted that it is not described as a subgroup of RA, but as adult onset Still's disease. There is no adult equivalent of the antinuclear antibody (ANA) positive pauciarticular form of JCA which makes up the majority of children with JCA. However, since they very rarely require treatment with second line drugs, they will not be discussed further. It is clear therefore that there are substantial differences between JCA and RA justifying a fresh look at our approach and rationale behind using disease-modifying agents.
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STUDIES USING SECOND LINE AGENTS The vast majority of studies looking at the effects of second line agents in JCA are retrospective. Although they have given us useful information regarding sideeffects, they have been of minimal value with regard to efficacy. There are several reasons which, although obvious, need to be stressed. The placebo effect cannot be over-stated. In recent USA/USSR prospective placebo-controlled studies in JCA the placebo effect ranged from 42-68% [18,19] (depending on the parameter studied). Although this striking effect is difficult to wholly explain, we must keep it in mind when analysing other studies which do not contain a placebo group or in retrospective studies. 'Regression towards the mean'. Patients are usually placed on 'study' drugs when their disease is active or difficult to control. Since statistically they are more likely to improve than deteriorate — especially in a disease characterized by exacerbations and remissions — a control population is essential. 'Inter observer variation'. Many retrospective studies are the cumulative findings obtained over many years when treatment criteria were not standardized and where the subsequent assessing clinicians varied. 'Communal therapy'. Until relatively recently the results of children with systemic and polyarticular disease were interpreted together. It is clear that these are different diseases and thus, lack of selection may confuse the findings. 'Noli Nocere?' In this age of patient enlightenment and alternative medicine we too must prove that our treatments are better than no treatment. This of course is easily said, but extremely difficult to do. In adult studies of RA where patients are more numerous and easier to recruit, therapeutic facts are still elusive. We must be grateful to those clinicians who organize multicentre prospective placebo-controlled studies in children for, although extremely difficult to do, they are essential.
Gold Multiple mechanisms of action of gold have been defined in vitro, however, the mechanisms by which it induces disease remission has yet to be proven. In vitro it inhibits prostaglandin biosynthesis, and interestingly gold accumulates in inflamed, but not non-inflamed synovial tissue [2]. It inhibits cell migration and phagocytosis at the site of inflammation. Evidence for immunomodulation include reduction in immunoglobulin levels following therapy. In vitro studies have shown impairment of antigen and mitogen responsiveness of mononuclear cells primarily by altering the function of antigen presenting cells, but possibly by altering terminal B cell differentiation. Since the synovial membrane (SM) in JCA resembles a cell-mediated immune response with activated macrophages and T cells, it would not seem unreasonable to expect gold in this circumstance to exhibit immunomodulating properties. There has however been no in vitro work looking at the effects of gold on mononuclear cell function in JCA. Since we know that the ratios of immunologically competent cells are different in childhood when compared to adulthood, it is probably unwise to assume that the results of such studies in JCA would be the same as those observed in adult RA. However, from the patient and their families point of view, the only important question is do they get better! There are no prospective placebo-controlled studies in the use of injectable gold. There have been 12 retrospective or open-controlled studies with a population of 374 [21]. These studies are difficult to compare since some children had failed on other second line agents, some included children with pauciarticular disease whilst in others the type of onset was not defined. Finally, definition of remission or improvement varied widely between studies. However, even if we generously assume that the outcome criteria are comparable, the results are widely disparate with remission rates varying from 0 to 57% [22,23] with improvement from 18 to 78% [21,24]. Looking at the mean improvement in these studies, the results are disappointing and no better than reported placebo improvements seen in other placebo-controlled studies of approximately 50% It is therefore not clear that gold is effective in the treatment of JCA. One thing is however clear and that is that gold is toxic during the febrile systemic phase of systemic JCA with reported significant side-effects at 58% and no obvious clinical benefit [25-27]. The benefit of gold in the polyarticular phase of systemic JCA is not impressive, but the toxicity appears to be halved. Most paediatric rheumatologists would, on personal experience, feel that gold therapy has a role in these diseases perhaps in the small group of children with RF-positive JCA. Since this disease is identical to, and often more severe than adult RA, its use is reasonable, but in the absence of a prospective placebo-controlled or 'case of one' studies, the efficacy of gold in the subgroups of JCA will remain unknown. Oral gold
The oral triethylphosphine gold preparation, aura-
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However, there is an increasing interest in the role of soluble mediators of the immune/inflammatory response. Cytokines and their receptors are undoubtedly important in the inflammatory arthritides. In pauci- and poly-articular JCA plasma IL-1, IL-6 and TNF (the inflammatory cytokines), all correlate with disease activity [14]. In contrast in systemic JCA no such correlation exists. Here IL-1 is inversely proportional to fever, whilst fever rises with rising IL-6 levels. Further IL-1 producing cells can be detected within the peripheral blood of children with afebrile systemic JCA [15], whilst Prieur et al. found low levels of IL-1 activity during the peaks of fever [16]. These are some of the first indications that levels of immuno/ inflammatory mediators vary in different disease subtypes. One explanation for the low levels of IL-1 detected during fever in systemic JCA are the high levels of the IL-1 receptor antagonist (IL-lra) known to be present [17]. Although at an embryonic stage the use of soluble receptors as disease modulators is now a reality.
ROONEY: A DISEASE-MODIFYING DRUG FOR JCA?
Anti-malarials Hydroxychloroquine sulphate is the most widely used of the 4-aminoquinolines due to the lower incidence of toxicity when compared to other chloroquine compounds. It has a variety of actions pertinent to inflammatory arthropathies including inhibition of antigen antibody reactions, inhibition of protein synthesis in activated cells via the inhibition of both DNA and RNA. It probably impairs the migration of neutrophils to the site of inflammation by inhibiting neutrophil chemotaxis. It may also have an anti-inflammatory effect by interfering in the prostaglandin pathways. Hydroxychloroquine is one of the few drugs which has been assessed in a prospective placebo-controlled study. The results were disappointing. In the USA/ USSR double-blind placebo-controlled trial [18], 162 children received either 6mg/kg of hydroxychloroquine/day or lOmg/kg D-penicillamine/day or placebo. All children improved, in particular there was no difference between the treated groups and the placebo groups, except pain on movement where hydroxychloroquine was significantly superior. There was a similar fall in ESR in all three groups. Of particular interest was toxicity; the incidence of leucopenia, haematuria and proteinuria were remarkably similar in all three groups. Proteinuria was observed in 13 patients, two on D-penicillamine, seven on hydroxychloroquine and four on placebo. Only three children dropped out as a result, one from each group, although the penicillamine-treated child developed reversible nephrotic syndrome. Indeed more dropped out of the placebo group — not as one might expect from inefficacy, but from toxicity!
We have anecdotal reports of a small population of children with RF-positive polyarticular JCA seroconverting while on hydroxychloroquine. In the USA/ USSR study only nine children who completed the study were RF-positive. Here again a similar decrease in RF titres were observed in all three groups. Although retinopathy continues to be a worry for clinicians using anti-malarials, no cases were seen in the USA/USSR study. This may simply indicate the relatively short duration of the trial. However, reviewing recent retrospective studies, keratopathy does exist [18,31], but was rarely considered to be clinically significant and was managed by lowering the dose. Earlier studies have reported serious retinopathy [32] and although these occurred in high dosage regimens than are used today, we still recommend biannual ophthalmologic assessment. Methotrexate Methotrexate, a dihydrofolate reductase inhibitor, interferes in the addition of new carbon units in the synthesis of DNA. Its effectiveness is thus expected to be dependent on cellular activity. This drug has only relatively recently been introduced into paediatric rheumatology, although it has been used in adult rheumatology for many years. In a double-blind placebocontrolled adult study there was significant improvement in the treated population [33] in a dose range of 7.5 to 15mg weekly. However, improvement could not be explained on the basis of immune modulation. There was no reduction in immunoglobulin production , cellular subsets response to soluble recall antigens or thymidine incorporation by peripheral blood cells following lectin stimulation. Thus the therapeutic efficacy of low dose methotrexate cannot be attributed to its mode of action in high dose (anti-cancer) regimes. The rapid action of methotrexate suggests that it has anti-inflammatory properties. Segal et al. [34] have demonstrated a rapid fall in CRP and ESR following a single low dose injection of methotrexate in patients with RA [34]. They have further shown that low dose methotrexate does not inhibit IL-1 production either in vitro or in vivo. However, it does inhibit the effect of IL-1 on a variety of normally responsive cell lines. Further, Miller et al. [36] have reported inhibitory "activity of methotrexate on IL-1, especially IL-ip apparently by competitive binding for the IL-1 receptor on T cells. Since the N terminal of IL-1(3 has 60% homology, with dihydrofolate reductase, they have suggested that binding of methotrexate to IL-1 may impair its activity. High levels of proteinases and collagenase released from the SM and detectable in the synovial fluid (SF) undoubtedly contribute to bone and cartilage destruction seen in the inflammatory arthritides. Pelletier et al. [37] have shown that patients treated with low dose methotrexate exhibited marked reduction in proteolytic and collagenalytic enzyme activity in SM specimens. Methotrexate may interfere with IL-1-induced neutrophil chemotaxis to the sites of inflammation within the joints and this may indirectly or directly
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nofin was introduced into clinical medicine in 1976. A number of early retrospective studies confirmed the safety of this product [28-30] with diarrhoea being the most frequent side-effect, although as many as onethird of children developed tachyphaxis late in the treatment. In these early open studies efficacy of auranofin was promising, however, in the large USA/USSR double-blind, placebo-controlled trial of 231 children [19], 69% of the auranofin treated patients and 61% of the placebo-treated patients demonstrated a clinically significant improvement after 6 months. It could be argued that had the trial continued beyond 6 months there would have been greater differences between the two groups. The dramatic placebo effect should be noted and although there was a tendency for the auranofin-treated group, to do better, this may be related to their higher base line articular disease scores. Thus on the evidence to date auranofin does not appear to be significantly better than non-steroidal anti-inflammatory drugs (NSAIDs). I use the latter term advisedly since in no study is there a true placebo group i.e. all children received NSAIDs. In the USA/USSR collaborative studies disease activity improved and erythrocyte sedimentation rate (ESR) and RF titres fell in the NSAID-treated group perhaps suggesting that these drugs do have disease-modifying properties?
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D-Penicillamine D-Penicillamine is a powerful chelating agent, and appears to have neither anti-inflammatory nor cytotoxic activities. It has few proven immunomodulating activities, although in prolonged administration immune complexes are cleared from both serum and SF. Since immune complexes and activated complement components are detectable in JCA, in particular those with disease of systemic onset, it could be anticipated D-penicillamine would be a useful drug. There have been 10 studies of penicillamine treatment in JCA [21], of these two were prospective placebo-controlled [18, 42]. The results of these studies are conflicting. In their study of 38 children, Prieur et al. [42] found that penicillamine was moderately more effective than placebo. However, in the USA/USSR
trial placebo was just as effective as penicillamine. The differences can possibly be attributed to study design. In the former steroids and NSAIDs could vary according to the patient's response and were used as outcome measures of efficacy. In the latter study steroids were excluded and the NSAID dose kept constant. The USA/USSR trial is probably more reliable. Using changes in other drug therapies as a measure of response adds another interobserver variable and perhaps confuses the issue. The efficacy of D-penicillamine in the treatment of JCA is dubious and therefore its use has more or less ceased. The toxicity of penicillamine is well reported in patients, e.g. proteinuria, bone marrow suppression. However, the side-effects of D-penicillamine observed in the USA/USSR study [18] were little different to those observed in the placebo group with the exception of the one child who developed nephrotic syndrome. Sulphasalazine This analogue of 5-amino-salacilic acid co-valently bound by an azo group to sulphapyridine has in recent years gained renewed popularity in both adult and childhood arthritis. The active anti-rheumatic moiety is probably the thiol portion. Despite the salicylic acid component, sulphasalazine has neither analgesic or antipyretic activity in the dosage regimens used in arthritis. Opinion is split on its mode of action. Some favour the alteration in GI tract flora (and perhaps antigenic load) as its mode of action in inflammatory arthritis [43], whilst other favour its effect on both the cyclo-oxygenase and lipoxygenase pathways [44]. There is reasonable consensus that it causes no direct immunomodulation [45]. There have been only three studies on the use of sulphasalazine in JCA [21,46,47]. Ozdogan et al. [46] studied 18 children with JCA in an open study (seven pauci, seven poly, four systemic). Unfortunately no comment was made regarding B27 status. An excellent response was observed in 11 patients (61%). Only three patients was there no improvement seen and two of these came from the systemic cohort of four. JobDeslandre et al. [47] reported their retrospective findings on 20 children with spondyloarthropathy. Marked clinical improvement was observed in 19 and NSAIDs were stopped in almost 50% Although these reports were not placebo-controlled, they are very encouraging. Hopefully current placebo-controlled studies in this B27 positive population will confirm their findings. Since in childhood the spondyloarthropathies are a group of overlapping diseases often difficult to differentiate with various degrees of GI tract involvement, it is interesting to consider the alteration of GI flora and possibly antigenic load as a possible explanation for its apparent increased efficacy in this group of diseases. Toxicity is seen in approximately 37% of children necessitating drug withdrawal in 10% The profile is the same as that seen in adults GI tract disturbance, skin reaction and haematologic disturbance including bone marrow suppression. Sulphasalazine like most of the DMARDs appears to have little effect in systemic
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lower the production and release of these enzymes within the joint. In recent years there have been a number of encouraging reports on the effectiveness of methotrexate in the treatment of JCA. Giannini etal. [38] in a prospective placebo-controlled study of 66 children (88% poly; 12% systemic), showed significant improvement in severity scores in the high dose methotrexate group (10mg/m2) over the placebo group. Speckmaier et al. [39] in a prospective non-placebo-controlled study of 12 children with intractable systemic JCA showed a modest improvement in both systemic and articular features, although there was a suggestion that methotrexate was more effective in alleviating the articular features. However, in the absence of a placebo group the 30% improvement quoted is not impressive, We are currently undertaking a multicentre prospective placebo-controlled crossover study on children with systemic and extended pauciarticular JCA. It would appear then that methotrexate in a dose of at least 10mg/m2 is an effective treatment for children with polyarticular JCA. Hopefully our study will clarify whether methotrexate is effective in systemic and extended pauciarticular disease. Side-effects are well-documented in methotrexate: hepatic toxicity and bone marrow suppression, gastrointestinal (GI) ulceration, diarrhoea and alopecia [40]. Significant renal and neurological abnormalities do not occur. Approximately 1% of adults develop an interstitial pneumonitis on methotrexate therapy [41]. Therefore regular monitoring of lung, hepatic function as well as full blood counts are necessary. Although oncogenicity has not been reported in children treated at high dosage and impairment of fertility does not appear to be a severe problem, long-term studies will need to be performed on fertility, oncogenicity, and the effect of these drugs on the progeny of our patients. Methotrexate would appear to be superior to other disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of JCA and many centres including our own are increasingly using this drug as their first choice of second line agent. It is paramount that this growing body of children are meticulously monitored in both the long- and short-term.
ROONEY: A DISEASE-MODIFYING DRUG FOR JCA? JCA. Side-effects appear to be more common during active systemic disease. An as yet unpublished UK study suggests that sulphasalazine is contra-indicated in systemic onset JCA.
systemic JCA and in young/recently diagnosed children, but is less effective in established disease and older children. Hopefully we will know whether this reflects clinical acumen or therapeutic bias from the soon to be published Canadian study. FUTURE THERAPY Our knowledge of the functioning of the immune system and of mediators of tissue destruction has increased exponentially since the introduction of current treatment of JCA. Although we do not know what the causative agents are, we can define the subsequent cell and humoral mediated immune response. It is true that we do not know whether these responses themselves are, on the one hand harmful or on the other suboptimal, we are now in a position to specifically target events in the immune response. The highly successful transplant therapies have opened up a whole new field of therapeutic intervention, some of which are currently undergoing phase II trials in rheumatology. Assuming that JCA is an antigen-mediated disease, ideal therapies would include competitive peptides to or antibodies directed against the MHC class II molecule, the T cell receptor or the various adhesion molecules such as ICAM1 which are involved in the early events of antigen recognition and processing. AntiICAM antibodies are among the most potent immunosuppressants. However, peptide therapies which have been effective in diseases where the antigen is known such as experimental allergic encephalomyelitis (EAE) will not be applicable in JCA until specific MHC and TCR peptide recognition sites are denned. Following initial antigen processing and T cell recruitment, antibodies against the T cell population e.g. anti-CD4 monoclonal antibodies may be effective. Uncontrolled studies in RA have been hopeful, although the depletion of CD4 positive cells observed were not matched by clinical improvement. Furthermore, because the effect is transient, treatment would need to be repeated, and since neither chimeric nor humanized antibodies completely abrogate the development of possible neutralizing anti-idiotypic antibodies, development of these will render the treatment less effective. Induction of a state of tolerance to any putative antigen is a highly attractive approach, since it avoids the need for long-term immunosuppression, but as neither the peptide nor specific diseaseassociated T cell clones have been defined in JCA, the development of a T cell vaccine remains hypothetical. Furthermore, since 'T cell' vaccination is known autoimmune diseases such as EAE is only really effective either before or at the onset of the disease, their use in an insidious and chronic disease such as JCA may prove inappropriate. Less specific therapies directed against T cell maturation such as cyclosporin A or rapamycin which are potent inhibitors of IL-2 and IL-2 receptor signal transduction may be of value in controlling established disease. To date cyclosporin A has not been used widely due to its renal toxicity. Further evaluation of toxicity vs. efficacy needs to be undertaken.
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Gammaglobulin It is clear from the above text that whereas a number of DMARDs appear to be moderately effective in the treatment of polyarticular onset JCA, few if any show a beneficial effect on the articular or the extra-articular features of systemic JCA. Indeed toxicity is so high during the systemic phase of this disease that in our opinion DMARDs are contra-indicated. One is left therefore with NSAIDs and steroids. Whilst the latter are indispensable in controlling the systemic features of systemic JCA and whilst in some children the disease can be controlled on very modest doses of steroids, there is a population in whom unacceptably high levels of steroids are required leading to growth retardation, osteoporosis and obesity. Attempted reduction in the steroids may lead to an exacerbation of the disease. In the last five years there has been a growing interest in the use of gammaglobulin treatment for systemic JCA. Originally used only for hypogammaglobulinaemic states and transmission of passive immunity, the repertoire of diseases for which it has been used had gradually increased to include idiopathic thrombocytopenic purpura [48,49], myasthenia gravis and most recently and spectacularly (in rheumatological terms) in Kawasaki disease [50]. The mechanism of action of i.v. gammaglobulin is not clear. Workers have shown that IgG can block the FC receptor of phagocyte cells, impair immune complex formation and binding, and down regulate B cell differentiation and thus IgG production [51-53]. Since i.v. gammaglobulin has been shown to be effective in a variety of immune complex mediated diseases, the above would seem a reasonable hypothesis for mechanism of action in vivo. Although systemic JCA is not thought to be an immune complex mediated disease per se, circulating complexes can be detected. Many abnormalities in T and B cell function have been reported in systemic JCA, and hypergammaglobulinaemia is a characteristic feature of the disease. Whether this reflects an over-stimulated intact immune response or an inadequate immune response despite polyclonal B cell activation, is not known. In any event administration of exogenous immune competent gammaglobulin could in theory correct either abnormality. Silverman etal. [54] in their pilot study treated eight children with active disease and on a variety of steroid regimens with gammaglobulin. It appeared to be most effective for extra-articular features with resolution in fever in six out of seven and improvement in rash in five out of six, allowing the discontinuation of steroid therapy in three with a reduction of 50% in a further three. Longer term follow-up of these children revealed that methotrexate was administered in three to control polyarthritis. Our anecdotal experience and personal communications suggest that i.v. gammaglobulin is valuable, particularly in the extra-articular features of
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REFERENCES
1. Brewer EJ, Bass J, Baum J, et al. Current proposed revision of JRA criteria. Arthritis Rheum 1977;20:195. 2. TsokosGC, InghiramiG, PillemerSR,e/a/. Immunoregulatory aberration in patients with polyarticular juvenile rheumatoid arthritis. Clin Immunol Immunopathol 1988;47:62-74. 3. Alspaugh MA, Miller JJ. A study of specificities of antinuclear antibodies in juvenile arthritis. J Pediatr 1977;90:391-5. 4. Bianco NE, Panush RS, Stillman JS, et al. Immunologic studies of juvenile rheumatoid arthritis. Arthritis Rheum 1971;14:685-96. 5. Martini A. Immunological abnormalities in juvenile chronic arthritis. Scand J Rheumatol 1987; 66:107-18. 6. Bergroth V, Knottinen YT, Pelkonen P, etal. Synovial fluid lymphocytes in different subtypes of juvenile rheumatoid arthritis. Arthritis Rheum 1988; 31:780-3. 7. Odum N, Morling N, Platz P, et al. Increased prevalence of late stage T cell activation antigen (VLA-1) in active juvenile chronic arthritis. Ann Rheum Dis 1987;46:846-52. 8. Morimoto C, Reinherz EL, Borel Y, et al. Autoantibody to an immuno-regulatory inducer population in patients with juvenile rheumatoid arthritis. J Clin Invest 1981,67:753-61. 9. Barron KS, Lewis DE, Brewer EJ, et al. Cytotoxic anti-T cell antibodies in children with juvenile rheumatoid arthritis. Arthritis Rheum 1984;27:1272-80. 10. De Vere-Tyndall A, Knight S, Burman S, et al. Lymphocytes responses in juvenile chronic arthritis and Behcet's disease — cell number requirements and effects of glucocorticosteroid therapy. Clin Exp Immunol 1982;50:549-54.
11. Hoyeraal HM. Impaired delayed hypersensitivity in juvenile rheumatoid arthritis. Ann Rheum Dis 1973;32:331-6. 12. Gershwin ME, Haselwood D, Dorshkind K, et al. Altered responsiveness in mitogens in subgroups of patients with juvenile rheumatoid arthritis. J Clin Lab Immunol 1978;l:293-7. 13. Williams RJ Jr, Froelich CJ, Kilpatrick K, etal. Tycell subset specificity of lymphocyte reactive factors in juvenile rheumatoid arthritis and systemic lupus erythematosus sera. Arthritis Rheum 1981; 24:585-91. 14. David J, Rooney M, Symons J, etal. Cytokines in juvenile chronic arthritis. In preparation. 15. Rooney M, Prieur A-M. Soluble ILla production in juvenile chronic arthritis. Arthritis Rheum 1990; abstract. 16. Prieur AM, Kaufmann MT, Griscelli C, etal. Specific Interleukin-1 inhibitor in serum and urine of children with systemic juvenile chronic arthritis. Lancet 1987;ii:1240-2. 17. Dinarello CA, Rosenwasser LJ, Wolff SM. Demonstration of a circulating suppressor factor of thymocyte proliferation during endotoxin fever in humans. J Immunol 1981;127:2517-19. 18. Brewer EJ, Giannini EH, Kuzmina N, et al. Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. Results of the USA-USSR double-blind placebo-controlled trial. N EnglJ Med 1986,314:1269-76. 19. Giannini EH, Brewer EJ Jr, Kuzmina N. Auranofin in the treatment of juvenile rheumatoid arthritis. Arthritis Rheum 1990;33:466-76. 20. Vernon Roberts B, Dore JL, Jessop JD, Henderson WJ. Selective concentration and localization of gold in macrophages of synovial and other tissue during and after cryotherapy in rheumatoid arthritis. Ann Rheum Dis 1976;35:477-86. 21. Grondin C, Malleson P, Petty RE. Slow-acting antirheumatic drugs in chronic arthritis of childhood. Semin Arthritis Rheum 1988;18:38-47. 22. Brewer EJ, Giannini EH, Barkley E. Gold therapy in the management of juvenile rheumatoid arthritis. Arthritis Rheum 1980;23:404-ll. 23. Debendetti C, Tretbar H, Corrigan JJ. Gold therapy in rheumatoid arthritis. Ariz Med 1976;33:373-6. 24. Sairanen E, Laaksonnen AL. The results of gold therapy in juvenile rheumatoid arthritis. Ann Pediatr Fenn 1964;10:274-9. 25. Hadchouel M, Prieur A-M, Griscelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: Possible relationship to drugs or infection. J Pediatr 1985;106:561-6. 26. Silverman ED, Miller JJ, Bernstein B, et al. Consumption coagulopathy associated with systemic juvenile rheumatoid arthritis. J Pediatr 1983; 103:872-6. 27. Manners PJ, Ansell BM. Slow-acting antirheumatic drug use in systemic onset juvenile chronic arthritis. Pediatrics 1986;77:99-103. 28. Giannini EH, Brewer EJ, Person DA. Auranofin in the treatment of juvenile rheumatoid arthritis. J Pediatr 1983;102:138-41. 29. Brewer EJ, Giannini EH, Person DA. Early experience with auranofin in juvenile rheumatoid arthritis. Am J Med 1983;75:152-6. 30. Giannini EH, Brewer EJ, Person DA, et al. Longterm auranofin therapy in patients with juvenile rheumatoid arthritis. J Rheumatol 1986;13:768-70.
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Since IL-1, TNF|3 and IL-6 are fundamental mediators of the inflammatory process and are involved in the immune response, cytokine or anti-cytokine therapy is an attractive proposition. However, since no cytokine works in isolation but rather as part of a network or cascade, the effect of such therapies are difficult to predict. High levels of the above-mentioned cytokines can be detected in the plasma and SF of children with polyarticular JCA. Anti-inflammatory cytokines such as interferon y, IL-4 and TGFp down regulate T cell activation, but upregulate other inflammatory mediators such as IL-6, thus reflecting the very complex nature of this network. Naturally occurring anti-cytokines such as soluble IL-1 and TNFa receptors block the action of the respective cytokines. The clinical importance of these naturally occurring antagonists can be seen in meningococcal septicaemia where a high TNFa to its natural inhibitor, the soluble TNFa receptor ratio is associated with higher mortality. Our preliminary results show that high levels of the IL-1 receptor antagonist are produced during the fever of systemic JCA, but the agonist/antagonist ratio of IL-1 and IL-lra may also be important in the pathogenesis and prognosis of this disease. Therefore, until we understand more fully the cytokine network in JCA, it is premature at this point to use naturally occurring antagonists in the treatment of JCA.
ROONEY: A DISEASE-MODIFYING DRUG FOR JCA?
43. West B, Lendnoon R, Hill HJ, Walker G. Effects of sulphasalazine (salazopyrin) on faecal flora in patients with inflammatory bowel disease. Gut 1974; 15:90-65. 44. Peskar BM, et al. Enhanced formation of sulfidopeptide leucotuenes in ulcerative colitis and Crohns disease: inhibition by sulphasalazine and 5-amino salicylic acid. Agents Actions 1986;18:381-3. 45. Thayer WR Jr, Carland C, Field CE. Effects of sulphasalazine on selected lymphocyte subpopulations in in vivo and in vitro. Dig Dis Sci 1979;241:672. 46. Ozdogan H, Turunc M, Deringol B, etal. Sulphasalazine in the treatment of juvenile rheumatoid arthritis. A preliminary open trial. / Rheumatol 1986;13:124-5. 47. Job-Deslandre C, Menkes CJ. Sulphasalazine in the treatment of juvenile spondyloarthropathy. Am Coll Rheumatol 1991; abstract C122. 48. Imbach P, Barandun S, d'Apuzzo V, etal. High-dose intravenous gamma-globulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981;i:1228-31. 49. WiniarskiJ, Krueger A, EjderhamnJ, etal. High dose intravenous IgG reduces platelet associated immunoglobulins and complement in idiopathic thrombocytopenic purpura. Scand J Hematol 1983; 31:342-8. 50. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gammaglobulin. N Engl J Med 1986;315:341-7. 51. Kurlander RJ, Hall J. Comparison of intravenous gammaglobulin and a monoclonal anti-F receptor antibody as inhibitors of immune complexes in vivo in mice. J Clin Invest 1986;77:2010-18. 52. Mannhalter JW, Ahmad R, Wolf HM, Eibl M: Effect on polymeric IgG on human monocyte functions. intArch Allergy Appl Immunol 1987;85:159-67. 53. Stohl W, Mayer L. Inhibition of T cell-dependent human B cell proliferation and B cell differentiation by polyspecific monomeric IgG. Clin Exp Immunol 1987;70:649-57. 54. Silverman ED, Laxer RM, Greenwald M, etal. Intravenous gammaglobulin therapy in systemic juvenile rheumatoid arthritis. Arthritis Rheum 1990; 33:1015-22.
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31. StillmanJS. Antimalarials in the treatment of juvenile rheumatoid arthritis. In: Moore TD (ed). Arthritb in childhood. Columbus: Ross Laboratories, 1981:125-7. 32. Rynes RI, Krohel G, Falbo A, et al. Ophthalmologic safety of long-term hydroxychloroquine treatment. Arthritis Rheum 1979;22:832. 33. Williams HJ, Wilkens RF, Samuelson, et al. Comparison of low dose oral pulsed methotrexate and placebo: the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 1985;28:721. 34. Segal R, Caspi D, Tishler M, etal. Short-term effects of low dose methotrexate on the acute phase reaction in patients with rheumatoid arthritis. / Rheumatol 1989;16:914-7. 35. Segal R, Mozes E, Yaron M, etal. The effects of methotrexate on the production and activity of IL-1. Arthritis Rheum 1989;32:370-7. 36. Miller LC, Cohen EE, Orencole SF, et al. Interleukin-ip is structurally related to dihydrofolate reductase: Effects of methotrexate on IL-1. Cytokine Res 1988;7:1.49 (abstract). 37. Pelletier JM, Clautier JM, Pelletier JP. In vivo effects of anti-rheumatic drugs on neutral collagenolytic proteases in human rheumatoid arthritis cartilage and synovium. J Rheumatol 1988;15:1198-1204. 38. Giannini EH, Brewer EJ. etal. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. N Engl J Med 326:1043-9. 39. Speckmaier M, Findeisen J, Woo P, et al. Low-dose methotrexate in systemic onset juvenile chronic arthritis. Clin Exp Rheumatol 1989;7:647-50. 40. Di Bartholomew AG, Mayes MD, Bathon JM. Methotrexate in rheumatoid arthritis: a longitudinal study of liver biopsies. Arthritis Rheum 1984;27:S61. 41. Searles G, McKendry RJR. Methotrexate pneumonitis in rheumatoid arthritis potential risk factors. Four case reports and a review of the literature. J Rheumatol 1987;14:1164. 42. Prieur AM, Piussan C, Manigne P, etal. Evaluation of D-penicillamine in juvenile chronic arthritis: A double-blind multicentre study. Arthritis Rheum 1985;28:376-82.
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IS THERE A DISEASE-MODIFYING DRUG FOR JUVENILE CHRONIC ARTHRITIS? BY M. ROONEY Molecular Rheumatology Section, MRC, Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ
PATHOGENESIS OF JUVENILE CHRONIC ARTHRITIS Since most of the adult therapies are aimed at depressing the synthesis of inflammatory mediators or immunosuppression, it is pertinent to examine the evidence for an immune reaction in JCA. To date JCA subgroups have been denned according to clinical rather than immunopathogenic differences and more recently immunogenetic studies have supported these divisions, suggesting a role for the immune response genes in JCA. Autoantibody production (ANA, rheumatoid factor (RF) and anti-lymphocytic antibodies) are present in various combination within the major subgroups [2-5], but are not unique to any one subgroup and are thus unlikely to be of aetiological significance (although we should not ignore their presence). A number of studies have explored lymphocyte phenotype and function in JCA with conflicting results. Normal and increased numbers of B cells have been found [2,6], although the B cell numbers in the study of Tsokos et al. [2] may have been an overestimation. Their observation that a significant population of these B cells were activated and exhibited suppressed responses to lectins and viral antigens is interesting. No consistent change in lymphocyte subsets has been observed. Some authors report normal CD4/8 ratios [7], whereas others report decreased ratios [8]. No consistent pattern has been observed with regard to disease subgroups or disease activity. However, Odum et al. [7] noted that there was an increase in the T cell population bearing late, but not early activation antigens suggesting chronic stimulation of this population of cells. Unfortunately they did not differentiate between the subpopulations of JCA. Barron et al. [9] found high levels of and T cell antibodies in the serum of almost all children with JCA irrespective of subgroup. Although there was only a slight and insignificant correlation between anti T cell antibody activity and disease activity, larger numbers of T cells reacted with JCA serum if they were activated first in vitro, suggesting that these antibodies were directed against activation antigens thus modulation the immune response. Again antigen and mitogen induced T cell responses have varied from study to study differences, perhaps being related to concomitant drug therapy [10-12]. One fairly consistent finding has been the presence of suppressor cytotoxic activity in JCA serum [9]. Whether this can be explained on the basis of anti T cell antibodies or immune complexes remains unclear [13]. © 1992 British Society for Rheumatology
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DISEASE-MODIFYING antirheumatic or second line drugs have been widely used in the treatment of juvenile chronic arthritis (JCA). The rationale for using these agents has been based on their efficacy in the treatment of adult rheumatic diseases. It is only in the last decade or so that we have re-classified the subgroups of JCA and research has shown quite clearly now that the immunopathology of childhood arthritis is somewhat different from that seen in adult disease. Juvenile chronic arthritis is divided into three major subgroups [1]. A fourth subgroup is gaining recognition in those with pauciarticular onset by a polyarticular course — extended pauci JCA. In approximately 40% of children the course of disease is polyarticular. In only 10% of cases are rheumatoid factors (RFs) detected when the disease closely resembles adult rheumatoid arthritis (RA) with a similar prevalence of the major histocompatibility antigen, HLA DR4 and an aggressive, erosive course. For the remaining 90%, the disease differs from adult RA. There is no association with HLA DR4. Erosions occur less frequently and joint ankylosis is more common. It is likely therefore that for the majority of children with polyarticular JCA the pathogenesis is different from that seen in adult RA. Thus it is probably inappropriate to assume that drugs which are effective in the latter will necessarily be useful in the former. Systemic JCA accounts for approximately 10% of the total population. Here again there are marked differences from adult RA. Rash and a characteristic high spiking fever are necessary for the diagnosis — very uncommon features in adult arthritides. Clinically significant visceral involvement is prominent in the former and usually absent in the latter. The sexes are affected equally in systemic JCA and, although some studies have reported an increased incidence of the HLA DR4 and Dw7 antigens, it has been disputed by others. An almost identical disease does occur but rarely in the adult population and it should be noted that it is not described as a subgroup of RA, but as adult onset Still's disease. There is no adult equivalent of the antinuclear antibody (ANA) positive pauciarticular form of JCA which makes up the majority of children with JCA. However, since they very rarely require treatment with second line drugs, they will not be discussed further. It is clear therefore that there are substantial differences between JCA and RA justifying a fresh look at our approach and rationale behind using disease-modifying agents.
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STUDIES USING SECOND LINE AGENTS The vast majority of studies looking at the effects of second line agents in JCA are retrospective. Although they have given us useful information regarding sideeffects, they have been of minimal value with regard to efficacy. There are several reasons which, although obvious, need to be stressed. The placebo effect cannot be over-stated. In recent USA/USSR prospective placebo-controlled studies in JCA the placebo effect ranged from 42-68% [18,19] (depending on the parameter studied). Although this striking effect is difficult to wholly explain, we must keep it in mind when analysing other studies which do not contain a placebo group or in retrospective studies. 'Regression towards the mean'. Patients are usually placed on 'study' drugs when their disease is active or difficult to control. Since statistically they are more likely to improve than deteriorate — especially in a disease characterized by exacerbations and remissions — a control population is essential. 'Inter observer variation'. Many retrospective studies are the cumulative findings obtained over many years when treatment criteria were not standardized and where the subsequent assessing clinicians varied. 'Communal therapy'. Until relatively recently the results of children with systemic and polyarticular disease were interpreted together. It is clear that these are different diseases and thus, lack of selection may confuse the findings. 'Noli Nocere?' In this age of patient enlightenment and alternative medicine we too must prove that our treatments are better than no treatment. This of course is easily said, but extremely difficult to do. In adult studies of RA where patients are more numerous and easier to recruit, therapeutic facts are still elusive. We must be grateful to those clinicians who organize multicentre prospective placebo-controlled studies in children for, although extremely difficult to do, they are essential.
Gold Multiple mechanisms of action of gold have been defined in vitro, however, the mechanisms by which it induces disease remission has yet to be proven. In vitro it inhibits prostaglandin biosynthesis, and interestingly gold accumulates in inflamed, but not non-inflamed synovial tissue [2]. It inhibits cell migration and phagocytosis at the site of inflammation. Evidence for immunomodulation include reduction in immunoglobulin levels following therapy. In vitro studies have shown impairment of antigen and mitogen responsiveness of mononuclear cells primarily by altering the function of antigen presenting cells, but possibly by altering terminal B cell differentiation. Since the synovial membrane (SM) in JCA resembles a cell-mediated immune response with activated macrophages and T cells, it would not seem unreasonable to expect gold in this circumstance to exhibit immunomodulating properties. There has however been no in vitro work looking at the effects of gold on mononuclear cell function in JCA. Since we know that the ratios of immunologically competent cells are different in childhood when compared to adulthood, it is probably unwise to assume that the results of such studies in JCA would be the same as those observed in adult RA. However, from the patient and their families point of view, the only important question is do they get better! There are no prospective placebo-controlled studies in the use of injectable gold. There have been 12 retrospective or open-controlled studies with a population of 374 [21]. These studies are difficult to compare since some children had failed on other second line agents, some included children with pauciarticular disease whilst in others the type of onset was not defined. Finally, definition of remission or improvement varied widely between studies. However, even if we generously assume that the outcome criteria are comparable, the results are widely disparate with remission rates varying from 0 to 57% [22,23] with improvement from 18 to 78% [21,24]. Looking at the mean improvement in these studies, the results are disappointing and no better than reported placebo improvements seen in other placebo-controlled studies of approximately 50% It is therefore not clear that gold is effective in the treatment of JCA. One thing is however clear and that is that gold is toxic during the febrile systemic phase of systemic JCA with reported significant side-effects at 58% and no obvious clinical benefit [25-27]. The benefit of gold in the polyarticular phase of systemic JCA is not impressive, but the toxicity appears to be halved. Most paediatric rheumatologists would, on personal experience, feel that gold therapy has a role in these diseases perhaps in the small group of children with RF-positive JCA. Since this disease is identical to, and often more severe than adult RA, its use is reasonable, but in the absence of a prospective placebo-controlled or 'case of one' studies, the efficacy of gold in the subgroups of JCA will remain unknown. Oral gold
The oral triethylphosphine gold preparation, aura-
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However, there is an increasing interest in the role of soluble mediators of the immune/inflammatory response. Cytokines and their receptors are undoubtedly important in the inflammatory arthritides. In pauci- and poly-articular JCA plasma IL-1, IL-6 and TNF (the inflammatory cytokines), all correlate with disease activity [14]. In contrast in systemic JCA no such correlation exists. Here IL-1 is inversely proportional to fever, whilst fever rises with rising IL-6 levels. Further IL-1 producing cells can be detected within the peripheral blood of children with afebrile systemic JCA [15], whilst Prieur et al. found low levels of IL-1 activity during the peaks of fever [16]. These are some of the first indications that levels of immuno/ inflammatory mediators vary in different disease subtypes. One explanation for the low levels of IL-1 detected during fever in systemic JCA are the high levels of the IL-1 receptor antagonist (IL-lra) known to be present [17]. Although at an embryonic stage the use of soluble receptors as disease modulators is now a reality.
ROONEY: A DISEASE-MODIFYING DRUG FOR JCA?
Anti-malarials Hydroxychloroquine sulphate is the most widely used of the 4-aminoquinolines due to the lower incidence of toxicity when compared to other chloroquine compounds. It has a variety of actions pertinent to inflammatory arthropathies including inhibition of antigen antibody reactions, inhibition of protein synthesis in activated cells via the inhibition of both DNA and RNA. It probably impairs the migration of neutrophils to the site of inflammation by inhibiting neutrophil chemotaxis. It may also have an anti-inflammatory effect by interfering in the prostaglandin pathways. Hydroxychloroquine is one of the few drugs which has been assessed in a prospective placebo-controlled study. The results were disappointing. In the USA/ USSR double-blind placebo-controlled trial [18], 162 children received either 6mg/kg of hydroxychloroquine/day or lOmg/kg D-penicillamine/day or placebo. All children improved, in particular there was no difference between the treated groups and the placebo groups, except pain on movement where hydroxychloroquine was significantly superior. There was a similar fall in ESR in all three groups. Of particular interest was toxicity; the incidence of leucopenia, haematuria and proteinuria were remarkably similar in all three groups. Proteinuria was observed in 13 patients, two on D-penicillamine, seven on hydroxychloroquine and four on placebo. Only three children dropped out as a result, one from each group, although the penicillamine-treated child developed reversible nephrotic syndrome. Indeed more dropped out of the placebo group — not as one might expect from inefficacy, but from toxicity!
We have anecdotal reports of a small population of children with RF-positive polyarticular JCA seroconverting while on hydroxychloroquine. In the USA/ USSR study only nine children who completed the study were RF-positive. Here again a similar decrease in RF titres were observed in all three groups. Although retinopathy continues to be a worry for clinicians using anti-malarials, no cases were seen in the USA/USSR study. This may simply indicate the relatively short duration of the trial. However, reviewing recent retrospective studies, keratopathy does exist [18,31], but was rarely considered to be clinically significant and was managed by lowering the dose. Earlier studies have reported serious retinopathy [32] and although these occurred in high dosage regimens than are used today, we still recommend biannual ophthalmologic assessment. Methotrexate Methotrexate, a dihydrofolate reductase inhibitor, interferes in the addition of new carbon units in the synthesis of DNA. Its effectiveness is thus expected to be dependent on cellular activity. This drug has only relatively recently been introduced into paediatric rheumatology, although it has been used in adult rheumatology for many years. In a double-blind placebocontrolled adult study there was significant improvement in the treated population [33] in a dose range of 7.5 to 15mg weekly. However, improvement could not be explained on the basis of immune modulation. There was no reduction in immunoglobulin production , cellular subsets response to soluble recall antigens or thymidine incorporation by peripheral blood cells following lectin stimulation. Thus the therapeutic efficacy of low dose methotrexate cannot be attributed to its mode of action in high dose (anti-cancer) regimes. The rapid action of methotrexate suggests that it has anti-inflammatory properties. Segal et al. [34] have demonstrated a rapid fall in CRP and ESR following a single low dose injection of methotrexate in patients with RA [34]. They have further shown that low dose methotrexate does not inhibit IL-1 production either in vitro or in vivo. However, it does inhibit the effect of IL-1 on a variety of normally responsive cell lines. Further, Miller et al. [36] have reported inhibitory "activity of methotrexate on IL-1, especially IL-ip apparently by competitive binding for the IL-1 receptor on T cells. Since the N terminal of IL-1(3 has 60% homology, with dihydrofolate reductase, they have suggested that binding of methotrexate to IL-1 may impair its activity. High levels of proteinases and collagenase released from the SM and detectable in the synovial fluid (SF) undoubtedly contribute to bone and cartilage destruction seen in the inflammatory arthritides. Pelletier et al. [37] have shown that patients treated with low dose methotrexate exhibited marked reduction in proteolytic and collagenalytic enzyme activity in SM specimens. Methotrexate may interfere with IL-1-induced neutrophil chemotaxis to the sites of inflammation within the joints and this may indirectly or directly
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nofin was introduced into clinical medicine in 1976. A number of early retrospective studies confirmed the safety of this product [28-30] with diarrhoea being the most frequent side-effect, although as many as onethird of children developed tachyphaxis late in the treatment. In these early open studies efficacy of auranofin was promising, however, in the large USA/USSR double-blind, placebo-controlled trial of 231 children [19], 69% of the auranofin treated patients and 61% of the placebo-treated patients demonstrated a clinically significant improvement after 6 months. It could be argued that had the trial continued beyond 6 months there would have been greater differences between the two groups. The dramatic placebo effect should be noted and although there was a tendency for the auranofin-treated group, to do better, this may be related to their higher base line articular disease scores. Thus on the evidence to date auranofin does not appear to be significantly better than non-steroidal anti-inflammatory drugs (NSAIDs). I use the latter term advisedly since in no study is there a true placebo group i.e. all children received NSAIDs. In the USA/USSR collaborative studies disease activity improved and erythrocyte sedimentation rate (ESR) and RF titres fell in the NSAID-treated group perhaps suggesting that these drugs do have disease-modifying properties?
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D-Penicillamine D-Penicillamine is a powerful chelating agent, and appears to have neither anti-inflammatory nor cytotoxic activities. It has few proven immunomodulating activities, although in prolonged administration immune complexes are cleared from both serum and SF. Since immune complexes and activated complement components are detectable in JCA, in particular those with disease of systemic onset, it could be anticipated D-penicillamine would be a useful drug. There have been 10 studies of penicillamine treatment in JCA [21], of these two were prospective placebo-controlled [18, 42]. The results of these studies are conflicting. In their study of 38 children, Prieur et al. [42] found that penicillamine was moderately more effective than placebo. However, in the USA/USSR
trial placebo was just as effective as penicillamine. The differences can possibly be attributed to study design. In the former steroids and NSAIDs could vary according to the patient's response and were used as outcome measures of efficacy. In the latter study steroids were excluded and the NSAID dose kept constant. The USA/USSR trial is probably more reliable. Using changes in other drug therapies as a measure of response adds another interobserver variable and perhaps confuses the issue. The efficacy of D-penicillamine in the treatment of JCA is dubious and therefore its use has more or less ceased. The toxicity of penicillamine is well reported in patients, e.g. proteinuria, bone marrow suppression. However, the side-effects of D-penicillamine observed in the USA/USSR study [18] were little different to those observed in the placebo group with the exception of the one child who developed nephrotic syndrome. Sulphasalazine This analogue of 5-amino-salacilic acid co-valently bound by an azo group to sulphapyridine has in recent years gained renewed popularity in both adult and childhood arthritis. The active anti-rheumatic moiety is probably the thiol portion. Despite the salicylic acid component, sulphasalazine has neither analgesic or antipyretic activity in the dosage regimens used in arthritis. Opinion is split on its mode of action. Some favour the alteration in GI tract flora (and perhaps antigenic load) as its mode of action in inflammatory arthritis [43], whilst other favour its effect on both the cyclo-oxygenase and lipoxygenase pathways [44]. There is reasonable consensus that it causes no direct immunomodulation [45]. There have been only three studies on the use of sulphasalazine in JCA [21,46,47]. Ozdogan et al. [46] studied 18 children with JCA in an open study (seven pauci, seven poly, four systemic). Unfortunately no comment was made regarding B27 status. An excellent response was observed in 11 patients (61%). Only three patients was there no improvement seen and two of these came from the systemic cohort of four. JobDeslandre et al. [47] reported their retrospective findings on 20 children with spondyloarthropathy. Marked clinical improvement was observed in 19 and NSAIDs were stopped in almost 50% Although these reports were not placebo-controlled, they are very encouraging. Hopefully current placebo-controlled studies in this B27 positive population will confirm their findings. Since in childhood the spondyloarthropathies are a group of overlapping diseases often difficult to differentiate with various degrees of GI tract involvement, it is interesting to consider the alteration of GI flora and possibly antigenic load as a possible explanation for its apparent increased efficacy in this group of diseases. Toxicity is seen in approximately 37% of children necessitating drug withdrawal in 10% The profile is the same as that seen in adults GI tract disturbance, skin reaction and haematologic disturbance including bone marrow suppression. Sulphasalazine like most of the DMARDs appears to have little effect in systemic
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lower the production and release of these enzymes within the joint. In recent years there have been a number of encouraging reports on the effectiveness of methotrexate in the treatment of JCA. Giannini etal. [38] in a prospective placebo-controlled study of 66 children (88% poly; 12% systemic), showed significant improvement in severity scores in the high dose methotrexate group (10mg/m2) over the placebo group. Speckmaier et al. [39] in a prospective non-placebo-controlled study of 12 children with intractable systemic JCA showed a modest improvement in both systemic and articular features, although there was a suggestion that methotrexate was more effective in alleviating the articular features. However, in the absence of a placebo group the 30% improvement quoted is not impressive, We are currently undertaking a multicentre prospective placebo-controlled crossover study on children with systemic and extended pauciarticular JCA. It would appear then that methotrexate in a dose of at least 10mg/m2 is an effective treatment for children with polyarticular JCA. Hopefully our study will clarify whether methotrexate is effective in systemic and extended pauciarticular disease. Side-effects are well-documented in methotrexate: hepatic toxicity and bone marrow suppression, gastrointestinal (GI) ulceration, diarrhoea and alopecia [40]. Significant renal and neurological abnormalities do not occur. Approximately 1% of adults develop an interstitial pneumonitis on methotrexate therapy [41]. Therefore regular monitoring of lung, hepatic function as well as full blood counts are necessary. Although oncogenicity has not been reported in children treated at high dosage and impairment of fertility does not appear to be a severe problem, long-term studies will need to be performed on fertility, oncogenicity, and the effect of these drugs on the progeny of our patients. Methotrexate would appear to be superior to other disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of JCA and many centres including our own are increasingly using this drug as their first choice of second line agent. It is paramount that this growing body of children are meticulously monitored in both the long- and short-term.
ROONEY: A DISEASE-MODIFYING DRUG FOR JCA? JCA. Side-effects appear to be more common during active systemic disease. An as yet unpublished UK study suggests that sulphasalazine is contra-indicated in systemic onset JCA.
systemic JCA and in young/recently diagnosed children, but is less effective in established disease and older children. Hopefully we will know whether this reflects clinical acumen or therapeutic bias from the soon to be published Canadian study. FUTURE THERAPY Our knowledge of the functioning of the immune system and of mediators of tissue destruction has increased exponentially since the introduction of current treatment of JCA. Although we do not know what the causative agents are, we can define the subsequent cell and humoral mediated immune response. It is true that we do not know whether these responses themselves are, on the one hand harmful or on the other suboptimal, we are now in a position to specifically target events in the immune response. The highly successful transplant therapies have opened up a whole new field of therapeutic intervention, some of which are currently undergoing phase II trials in rheumatology. Assuming that JCA is an antigen-mediated disease, ideal therapies would include competitive peptides to or antibodies directed against the MHC class II molecule, the T cell receptor or the various adhesion molecules such as ICAM1 which are involved in the early events of antigen recognition and processing. AntiICAM antibodies are among the most potent immunosuppressants. However, peptide therapies which have been effective in diseases where the antigen is known such as experimental allergic encephalomyelitis (EAE) will not be applicable in JCA until specific MHC and TCR peptide recognition sites are denned. Following initial antigen processing and T cell recruitment, antibodies against the T cell population e.g. anti-CD4 monoclonal antibodies may be effective. Uncontrolled studies in RA have been hopeful, although the depletion of CD4 positive cells observed were not matched by clinical improvement. Furthermore, because the effect is transient, treatment would need to be repeated, and since neither chimeric nor humanized antibodies completely abrogate the development of possible neutralizing anti-idiotypic antibodies, development of these will render the treatment less effective. Induction of a state of tolerance to any putative antigen is a highly attractive approach, since it avoids the need for long-term immunosuppression, but as neither the peptide nor specific diseaseassociated T cell clones have been defined in JCA, the development of a T cell vaccine remains hypothetical. Furthermore, since 'T cell' vaccination is known autoimmune diseases such as EAE is only really effective either before or at the onset of the disease, their use in an insidious and chronic disease such as JCA may prove inappropriate. Less specific therapies directed against T cell maturation such as cyclosporin A or rapamycin which are potent inhibitors of IL-2 and IL-2 receptor signal transduction may be of value in controlling established disease. To date cyclosporin A has not been used widely due to its renal toxicity. Further evaluation of toxicity vs. efficacy needs to be undertaken.
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Gammaglobulin It is clear from the above text that whereas a number of DMARDs appear to be moderately effective in the treatment of polyarticular onset JCA, few if any show a beneficial effect on the articular or the extra-articular features of systemic JCA. Indeed toxicity is so high during the systemic phase of this disease that in our opinion DMARDs are contra-indicated. One is left therefore with NSAIDs and steroids. Whilst the latter are indispensable in controlling the systemic features of systemic JCA and whilst in some children the disease can be controlled on very modest doses of steroids, there is a population in whom unacceptably high levels of steroids are required leading to growth retardation, osteoporosis and obesity. Attempted reduction in the steroids may lead to an exacerbation of the disease. In the last five years there has been a growing interest in the use of gammaglobulin treatment for systemic JCA. Originally used only for hypogammaglobulinaemic states and transmission of passive immunity, the repertoire of diseases for which it has been used had gradually increased to include idiopathic thrombocytopenic purpura [48,49], myasthenia gravis and most recently and spectacularly (in rheumatological terms) in Kawasaki disease [50]. The mechanism of action of i.v. gammaglobulin is not clear. Workers have shown that IgG can block the FC receptor of phagocyte cells, impair immune complex formation and binding, and down regulate B cell differentiation and thus IgG production [51-53]. Since i.v. gammaglobulin has been shown to be effective in a variety of immune complex mediated diseases, the above would seem a reasonable hypothesis for mechanism of action in vivo. Although systemic JCA is not thought to be an immune complex mediated disease per se, circulating complexes can be detected. Many abnormalities in T and B cell function have been reported in systemic JCA, and hypergammaglobulinaemia is a characteristic feature of the disease. Whether this reflects an over-stimulated intact immune response or an inadequate immune response despite polyclonal B cell activation, is not known. In any event administration of exogenous immune competent gammaglobulin could in theory correct either abnormality. Silverman etal. [54] in their pilot study treated eight children with active disease and on a variety of steroid regimens with gammaglobulin. It appeared to be most effective for extra-articular features with resolution in fever in six out of seven and improvement in rash in five out of six, allowing the discontinuation of steroid therapy in three with a reduction of 50% in a further three. Longer term follow-up of these children revealed that methotrexate was administered in three to control polyarthritis. Our anecdotal experience and personal communications suggest that i.v. gammaglobulin is valuable, particularly in the extra-articular features of
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BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXXI NO. 9
REFERENCES
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Since IL-1, TNF|3 and IL-6 are fundamental mediators of the inflammatory process and are involved in the immune response, cytokine or anti-cytokine therapy is an attractive proposition. However, since no cytokine works in isolation but rather as part of a network or cascade, the effect of such therapies are difficult to predict. High levels of the above-mentioned cytokines can be detected in the plasma and SF of children with polyarticular JCA. Anti-inflammatory cytokines such as interferon y, IL-4 and TGFp down regulate T cell activation, but upregulate other inflammatory mediators such as IL-6, thus reflecting the very complex nature of this network. Naturally occurring anti-cytokines such as soluble IL-1 and TNFa receptors block the action of the respective cytokines. The clinical importance of these naturally occurring antagonists can be seen in meningococcal septicaemia where a high TNFa to its natural inhibitor, the soluble TNFa receptor ratio is associated with higher mortality. Our preliminary results show that high levels of the IL-1 receptor antagonist are produced during the fever of systemic JCA, but the agonist/antagonist ratio of IL-1 and IL-lra may also be important in the pathogenesis and prognosis of this disease. Therefore, until we understand more fully the cytokine network in JCA, it is premature at this point to use naturally occurring antagonists in the treatment of JCA.
ROONEY: A DISEASE-MODIFYING DRUG FOR JCA?
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