Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases II
Glucocorticoids in juvenile idiopathic arthritis Clara Malattia and Alberto Martini Pediatria II, Istituto Giannina Gaslini, and Department of Pediatrics, University of Genova, Genova, Italy Address for correspondence: Alberto Martini, Pediatria II, Istituto Giannina Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy. [email protected]
Although the use of corticosteroids in juvenile idiopathic arthritis (JIA) is now much more limited owing to the availability of methotrexate and biological agents, there are clinical scenarios where it is still indicated. For example, corticosteroids may be indicated for intraarticular injections to prevent joint deformities, as a “bridge” drug to relieve symptoms in polyarticular disease while waiting for methotrexate and biologics to exert their full therapeutic effects, and in the treatment of chronic iridocyclitis, macrophage activation syndrome, and systemic JIA, although the advent of interleukin (IL)-1 and IL-6 blockers has greatly reduced the latter indication. Keywords: juvenile idiopathic arthritis; corticosteroids; intraarticular injections; systemic juvenile idiopathic arthritis; chronic iridocyclitis; macrophage activation syndrome
Introduction The use of corticosteroids in juvenile idiopathic arthritis (JIA) differs from that in rheumatoid arthritis (RA) for several reasons. First, JIA is not a disease, but an exclusion diagnosis that encompasses all forms of arthritis that begin before the age of 16 years, persist for more than 6 weeks, and are of unknown origin.1,2 This heterogeneous group of disorders has been classified on the basis of clinical and laboratory features to try to identify, for research purposes, homogeneous, mutually exclusive categories3 (Table 1). Systemic arthritis is considered the childhood equivalent of adult-onset Still’s disease. Rheumatoid factor (RF)+ arthritis is the same disease as in adults but represents a tiny minority of all JIA cases. Enthesitis-related arthritis is a form of undifferentiated spondyloarthropathy. Most patients with oligoarthritis, in Western countries, have a form that is not observed in adults and is characterized by an early onset and the positivity of antinuclear antibodies (ANAs). RF− polyarthritis and psoriatic arthritis are still heterogeneous conditions. Undifferentiated arthritis is not a separate subset but includes those patients who do not fit in any category or fit in more than one. Recent clinical and laboratory observations have provided new
insights that strongly suggest that while some JIA categories identify definite disease entities, others still include heterogeneous conditions;4,5 JIA is therefore much more heterogeneous than RA. Second, with the exception of RF+ JIA, it is often difficult to predict, at disease onset, the longterm outcome of the disease6 and therefore, a careful evaluation during follow-up is required. Third, any therapy in children should be considered in relation to the developing body and prolonged life expectancy. Statural growth suppression is one of the several well-known corticosteroid side effects and has, of course, great relevance in pediatrics. It occurs in children who are receiving prolonged therapy in doses greater than 0.2–0.3 mg/kg/day of prednisone, increases with higher doses, and is almost universally seen when divided doses are used.7,8 However, wide interindividual variation exists in the severity of growth suppression and in the minimal dose required to suppress growth. Finally, it has to be mentioned that not all drugs that are available in adults are registered for use in children. Indeed, until recently, controlled trials in subjects at pediatric ages were rare. The situation has dramatically changed owing to the implementation by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)
doi: 10.1111/nyas.12436 C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1318 (2014) 65–70
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Table 1. Frequency, age at onset, and sex distribution of the International League of Associations for Rheumatology (ILAR) categories of JIA
ILAR category
Frequency
Systemic arthritis Oligoarthritis Rheumatoid factor+ polyarthritis Rheumatoid factor− polyarthritis
5–15% 30–60% 3–7% 10–25%
Enthesitis-related arthritis Psoriatic arthritis
5–10% 3–10%
Undifferentiated arthritis
10–20%
Onset age Any pediatric age Early childhood Late childhood or adolescence Biphasic distribution; early peak 6 years Late childhood or adolescence Biphasic distribution; early peak 6 years –
Sex ratio F=M F >>> M F >> M F >> M M >> F F>M –
F, female; M, male.
of the “pediatric rule.” In brief, this rule states that if an industry wishes to register a new drug for a given disease, it has to provide data on safety and efficacy in children if an equivalent disease is also present at pediatric ages. Because of the pediatric rule, registrative trials for JIA have been performed for etanercept,9 adalimumab,10 abatacept,11 tocilizumab,12 and canakinumab.13 For the abovementioned reasons, in JIA corticosteroids have limited indications that will briefly be summarized. Intraarticular injections In a growing skeletal joint, contractures secondary to synovitis lead to deformity, as do joint contracture of the knee that causes a valgus deformity. Moreover, the unilateral involvement of the knee leads to a leg length discrepancy secondary to bone overgrowth on the affected side, likely in turn secondary to inflammation-induced hyperemia with release of growth factors. These anomalies that represented a major challenge in the past can now be effectively prevented by intraarticular steroid injections that induce a rapid relief of inflammation, restore function, and therefore interrupt the vicious circle leading to deformity.14 The long-acting steroid used worldwide is triamcinolone hexacetonide, which induces remissions that last much longer than those obtained with triamcinolone acetonide.15,16 The majority of patients show a remission of synovitis in the injected joint, lasting more than 6 months. However, for smaller joints or joints that are not easy to reach, the use of a more soluble corticosteroid drug is advisable.14 Imaging guidance (ultrasound) facilitates accurate placement of the needle within the 66
joint space, thus reducing the risk of side effects and maximizing the efficacy of the procedure. The most common adverse effect is subcutaneous atrophy at the site of injection, which is caused by delivery of the steroid preparation out of the joint space. This complication, which can usually be avoided with a careful injection technique, may resolve with time, although it can persist in some patients. The procedure can be performed in an ambulatory care setting, using local anesthesia with or without conscious sedation. Younger children or those who are candidates for multiple injections17 require general anesthesia. Chronic iridocyclitis Anterior uveitis, which involves the iris and the ciliary body (iridocyclitis), is a characteristic complication of JIA and occurs with much higher frequency in ANA+ patients.1,2 One or both eyes may be involved. The onset is insidious and often entirely asymptomatic, in contrast with the painful, acute iridocyclitis that is observed in spondyloarthropathies, such as enthesitis-related arthritis. Iridocyclitis usually occurs at the time of JIA diagnosis or thereafter, while it rarely precedes the onset of arthritis. The course may be relapsing or chronic and does not parallel the clinical course of arthritis. Because iridocyclitis is asymptomatic at onset, children with JIA should be screened periodically by slit-lamp examination. If the diagnosis is made early, topical steroids associated with mydiatrics are usually sufficient to control inflammation.18,19 Periocular subtenon injection of steroids are useful in cases where inflammation does not respond to topical
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therapy, and systemic steroids are indicated in case of ocular inflammation resistant to local treatments. Prednisolone is most commonly used at an induction dose of 1–2 mg/kg body weight, usually in a single morning dose that is then tapered on the basis of the clinical response. If systemic steroids fail to completely control ocular inflammation, immunosuppressants (particularly methotrexate (MTX)) and biologics (especially monoclonal antitumor necrosis factor (TNF-␣) antibodies) are indicated.18,19 It should be remembered that the long-term use of corticosteroids can cause cataracts and glaucoma. Corticosteroids as a bridge drug Experience with long-term low-dose prednisone, as in adult RA, is lacking in JIA. This is probably related to concerns about side effects, as well as to the difficulty of predicting long-term outcome at disease onset. Corticosteroids are used in severe polyarticular disease usually as a bridge drug. A short course of low-dose prednisone (0.5 mg/kg/day or less) is indeed indicated to alleviate pain and stiffness in patients with severe polyarthritis refractory to other therapies or while awaiting the full therapeutic effects of recently initiated MTX or biologic therapy. Corticosteroids are then progressively tapered and then suspended. This is now possible in the majority of patients owing particularly to the availability of biological agents, such as TNF-␣ blockers and abatacept. Multiple intraarticular injections with triamcinolone hexacetonide, with the same indications, may represent a valid alternative to the systemic administration of steroids. In a recently published study of a total of 220 patients who had 1096 joints injected, the cumulative probability of survival without synovitis flare was 50.0%, 31.5%, and 19.5% at 1, 2, and 3 years, respectively.17 Systemic JIA Systemic JIA (sJIA) has been, until recently, the main indication for long-term steroid therapy. As a consequence, this was also the disease in which the most severe side effects, ranging from permanent loss of stature to massive osteoporosis with extensive vertebral compression fractures, were more frequently observed. sJIA20,21 is characterized by the presence of a daily, high spiking fever, which is almost always associated with a salmon-colored evanescent,
Glucocorticoids in JIA
erythematous rash. Other extraarticular features include hepatomegaly and/or splenomegaly, generalized lymphoadenopathy, serositis (pericarditis and pleuritis), and laboratory abnormalities, such as neutrophilic leukocytosis, thrombocytosis, anemia, and elevated inflammatory markers. Systemic features of the disease may precede the onset of arthritis. The disease is observed at any pediatric age and affects children of both sexes with approximately equal frequency. It is considered the equivalent in children of adult-onset Still’s disease. The clinical course is highly variable; systemic features tend to recede during the initial months of the disease but may recur in case of disease relapse. About half of the patients eventually recover almost completely and usually with a good long-term prognosis. In the other half of the patients, the disease follows an unremitting course, with chronic arthritis representing the major long-term problem. The persistence of systemic features without arthritis is unusual. Markedly distinct clinical and laboratory features of sJIA suggest a different pathogenesis from the other forms of JIA. Prominent systemic features, a marked inflammatory response, an equal sex ratio, a lack of any association with human leukocyte antigen genes, and an absence of autoantibodies are all consistent with what is observed in autoinflammatory diseases.22 It is likely that sJIA is not a single disease but a syndrome that represents the terminal phase of different mechanisms all leading to a persistent activation of the innate immune system.5 Laboratory and clinical observations over the last 20 years have shown a major pathogenic role for interleukin (IL)-6 and IL-1 in sJIA and have laid the groundwork to implement new therapeutic strategies. In the 1990s, several laboratory studies23–26 led to the hypothesis that sJIA is an IL-6–driven disease.27 The major pathogenic role of IL-6 has been confirmed 10 years later by favorable results from a double-blind controlled study that demonstrated a marked efficacy of tocilizumab, a monoclonal antibody targeting the soluble IL-6 receptor in reducing systemic features and improving inflammatory arthritis in 56 patients with sJIA.28 More recently, the marked efficacy of tocilizumab has been confirmed compared to placebo in a controlled study performed in 112 patients with severe, persistent, and unresponsive sJIA.12
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The discovery of the important role of IL-1 in the etiopathogenesis of sJIA came from observation of the efficacy of the IL-1 receptor antagonist anakinra in the treatment of sJIA.29,30 The role of IL-1 is not in contradiction with the role of IL-6, because IL-1 is upstream to IL-6. Indeed, the use of such a drug in clinical practice has shown that the response to anakinra can identify two different subgroups of patients.31 One subgroup (accounting for approximately 40% of patients) with a dramatic response to IL-1 blockade (quite similar to that already observed in cryopyrinassociated autoinflammatory syndromes) is characterized by a prompt and complete normalization of clinical and laboratory features. The other subgroup has a resistant or incomplete response to anakinra, with a good response for systemic features but persistence of synovitis. The main differences observed between these two groups were in the number of joints involved and in neutrophils count; patients with fewer affected joints or with higher neutrophil counts had a high probability of responding to anti-IL-1 therapy. The therapeutic efficacy of anakinra has also been documented even in a controlled study.32 More recently, canakinumab, a monoclonal antibody against IL-1, proved to be effective in a dose-finding phase I/II trial33 and in a phase III trial in sJIA patients with active systemic features.13 These recent discoveries have radically changed the approach to the treatment of sJIA34 and have greatly reduced the need for long-term corticosteroid therapy. Indeed, both canakinumab and tocilizumab in many cases are sufficient to control the disease without the need for corticosteroids. From a practical point of view, during the diagnostic workup, patients are treated with nonsteroidal anti-inflammatory drugs. Once the diagnosis is made and if symptoms do not remit, as they typically do, steroid therapy is initiated (usually 2 mg/kg). If symptoms recur after a rapid steroid tapering, other therapies are indicated because the long-term use of steroids is associated with severe side effects. Different approaches are available to control the disease and reduce or withdraw steroids.35,36 If systemic symptoms no longer persist, treatment with MTX, anti-TNF-␣ agents, and abatacept can be indicated in sequence, although the results obtained with anti-TNF-␣ drugs have been less satisfactory in comparison with those observed 68
in the other forms of JIA (for abatacept there are still limited data).37 If systemic symptoms persist, either an anti-IL-1 or anti-IL-6 inhibitor is indicated. Usually, IL-1 inhibition is chosen as the first choice in patients in whom systemic features prevail over arthritis. As mentioned above, in many cases treatment is tapered and then corticosteroids are suspended. Recently, it has been suggested that early treatment with IL-1 inhibition could prevent the subsequent appearance of refractory arthritis in the large majority of patients. This hypothesis comes from observational studies and needs to be confirmed in prospective randomized trials.38,39 Macrophage activation syndrome For unknown reasons, children with sJIA are particularly susceptible to develop a life-threatening complication that occurs in around 6–8% of patients.40 This syndrome, called macrophage activation syndrome (MAS), is a form of reactive hemophagocytic lymphohistiocytosis and is characterized by sustained fever, pancytopenia, elevated transaminases and triglycerides, markedly increased ferritin concentrations, a coagulopathy with hemorrhagic manifestations, and neurologic symptoms. A bone marrow aspirate often shows the presence of phagocytosis of hematopoietic cells by macrophages. Specific criteria for the diagnosis of MAS in sJIA have been proposed and their validation process is ongoing.41,42 MAS is a medical emergency and should be promptly recognized and treated. Parenteral steroids in high divided doses in association with cyclosporine43,44 are usually able to control this complication if the diagnosis is prompt and the treatment rapidly instituted. Conclusions In conclusion, although the use of corticosteroids in JIA has been greatly reduced by the introduction of MTX and biological agents, there are clinical scenarios where it is still indicated. Intraarticular injections are essential in preventing deformities of the growing skeleton secondary to joint contracture. Multiple joint injections or systemic steroid can be used as a bridge drug to relieve symptoms in polyarticular disease while waiting for the effects of MTX and biologics. Furthermore, topical or systemic steroids are essential for the treatment of chronic anterior
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uveitis. Although systemic steroids keep their role in the treatment of sJIA, the advent of IL-1 and IL-6 blockers has greatly reduced their indication. Finally, steroids are essential, in combination with cyclosporine, in the therapy of MAS. Conflicts of interest
Glucocorticoids in JIA
17.
18.
The authors declare no conflicts of interest. 19.
References 1. Ravelli, A. & A. Martini. 2007. Juvenile idiopathic arthritis. Lancet 369: 767–778. 2. Prakken, B., S. Albani & A. Martini. 2011. Juvenile idiopathic arthritis. Lancet 377: 2138–2149. 3. Petty, R.E. et al. 2004. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 31: 390– 392. 4. Martini, A. 2003. Are the number of joints involved or the presence of psoriasis still useful tools to identify homogeneous disease entities in juvenile idiopathic arthritis? J. Rheumatol. 30: 1900–1903. 5. Martini, A. 2012 It is time to rethink juvenile idiopathic arthritis classification and nomenclature. Ann. Rheum. Dis. 71: 1437–1439. 6. Ravelli, A. & A. Martini. 2003. Early predictors of outcome in juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 21: S89–S93. 7. Ravelli, A., B. Lattanzi, A. Consolaro & A. Martini. 2011. Glucocorticoids in pediatric rheumatology. Clin. Exp. Rheumatol. 29: S148–S152. 8. Melo-Gomes, J.A. 1993. Problems related to systemic glucocorticoid therapy in children. J. Rheumatol. Suppl. 37: 35–39. 9. Lovell, D.J. et al. 2000. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N. Engl. J. Med. 342: 763– 769. 10. Lovell, D.J. et al. 2008. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N. Engl. J. Med. 359: 810–820. 11. Ruperto, N. et al. 2008. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebocontrolled withdrawal trial. Lancet. 372: 383–391. 12. De Benedetti, F. et al. 2012. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367: 2385–2395. 13. Ruperto, N. et al. 2012. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367: 2396–2406. 14. Scott, C. et al. 2010. A reappraisal of intra-articular corticosteroid therapy in juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 28: 774–781. 15. Zulian, F., G. Martini, et al. 2004. Triamcinolone acetonide and hexacetonide intra-articular treatment of symmetrical joints in juvenile idiopathic arthritis: a double-blind trial. Rheumatology (Oxford) 43: 1288–1291. 16. Eberhard, B.A., M.C. Sison, B.S. Gottlieb & N.T. Ilowite. 2004. Comparison of the intraarticular effectiveness of
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triamcinolone hexacetonide and triamcinolone acetonide in treatment of juvenile rheumatoid arthritis. J. Rheumatol. 31: 2507–2512. Papadopoulou, C. et al. 2013. Delineating the role of multiple intraarticular corticosteroid injections in the management of juvenile idiopathic arthritis in the biologic era. Arthritis Care Res. (Hoboken) 65: 1112–1120. Simonini, G. et al. 2010. Current therapeutic approaches to autoimmune chronic uveitis in children. Autoimmun. Rev. 9: 674–683. Heiligenhaus, A. et al. 2012. Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Rheumatol. Int. 32: 1121–1133. Mellins, E.D., C. Macaubas & A.A. Grom. 2011. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat. Rev. Rheumatol. 7: 416–426. Martini, A. 2012. Systemic juvenile idiopathic arthritis. Autoimmun. Rev. 12: 56–59. Masters, S.L., A. Simon, I. Aksentijevich & D.L. Kastner. 2009. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27: 621–668. De Benedetti, F. et al. 1991. Correlation of serum interleukin6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis. Rheum. 34: 1158–1163. Martini, A. et al. 1994. Intravenous iron therapy for severe anaemia in systemic-onset juvenile chronic arthritis. Lancet. 344: 1052–1054. Cazzola, M. et al. 1996. Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood 87: 4824–4830. De Benedetti, F. et al. 1997. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulinlike growth factor-I. A model for stunted growth in children with chronic inflammation. J. Clin. Invest. 99: 643–650. De Benedetti, F. & A. Martini. 1998. Is systemic juvenile rheumatoid arthritis an interleukin 6 mediated disease? J. Rheumatol. 25: 203–207. Yokota, S. et al. 2008. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371: 998–1006. Verbsky, J.W. & A. J. White. 2004. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J. Rheumatol. 31: 2071–2075. Pascual, V. et al. 2005. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J. Exp. Med. 201: 1479–1486. Gattorno, M. et al. 2008. The pattern of response to antiinterleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 58: 1505–1515. Quartier, P. et al. 2011. A multicentre, randomised, doubleblind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset
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juvenile idiopathic arthritis (ANAJIS trial). Ann. Rheum. Dis. 70: 747–754. Ruperto, N. et al. 2012. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis. Rheum. 64: 557– 567. Sandborg, C. & E.D. Mellins. 2012. A new era in the treatment of systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367: 2439–2440. Beukelman, T. et al. 2011. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis. Care. Res. (Hoboken). 63: 465– 482. Ringold, S. et al. 2013. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis. Rheum. 65: 2499– 2512. Quartier, P. et al. 2003. Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis. Rheum. 48: 1093–1101.
38. Nigrovic, P.A. et al. 2011. Anakinra as first-line diseasemodifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 63: 545–555. 39. Vastert, S.J. et al. 2013. Effectiveness of first line use of recombinant IL-1RA treatment in steroid na¨ıve systemic juvenile idiopathic arthritis: results of a prospective cohort study. Arthritis Rheum. DOI: 10.1002/art.38296. 40. Ravelli, A., A.A Grom, E.M. Behrens & R.Q. Cron. 2012. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes. Immun. 13: 289–298. 41. Ravelli, A. et al. 2005. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J. Pediatr. 146: 598–604. 42. Dav`ı, S. et al. 2011. MAS Study Group. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J. Rheumatol. 38: 764–768. 43. Ravelli, A., F. De Benedetti, S.Viola & A. Martini. 1996. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J. Pediatr. 128: 275–278. 44. Mouy, R. et al. 1996. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J. Pediatr. 129: 750–754.
C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1318 (2014) 65–70
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases II
Glucocorticoids in juvenile idiopathic arthritis Clara Malattia and Alberto Martini Pediatria II, Istituto Giannina Gaslini, and Department of Pediatrics, University of Genova, Genova, Italy Address for correspondence: Alberto Martini, Pediatria II, Istituto Giannina Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy. [email protected]
Although the use of corticosteroids in juvenile idiopathic arthritis (JIA) is now much more limited owing to the availability of methotrexate and biological agents, there are clinical scenarios where it is still indicated. For example, corticosteroids may be indicated for intraarticular injections to prevent joint deformities, as a “bridge” drug to relieve symptoms in polyarticular disease while waiting for methotrexate and biologics to exert their full therapeutic effects, and in the treatment of chronic iridocyclitis, macrophage activation syndrome, and systemic JIA, although the advent of interleukin (IL)-1 and IL-6 blockers has greatly reduced the latter indication. Keywords: juvenile idiopathic arthritis; corticosteroids; intraarticular injections; systemic juvenile idiopathic arthritis; chronic iridocyclitis; macrophage activation syndrome
Introduction The use of corticosteroids in juvenile idiopathic arthritis (JIA) differs from that in rheumatoid arthritis (RA) for several reasons. First, JIA is not a disease, but an exclusion diagnosis that encompasses all forms of arthritis that begin before the age of 16 years, persist for more than 6 weeks, and are of unknown origin.1,2 This heterogeneous group of disorders has been classified on the basis of clinical and laboratory features to try to identify, for research purposes, homogeneous, mutually exclusive categories3 (Table 1). Systemic arthritis is considered the childhood equivalent of adult-onset Still’s disease. Rheumatoid factor (RF)+ arthritis is the same disease as in adults but represents a tiny minority of all JIA cases. Enthesitis-related arthritis is a form of undifferentiated spondyloarthropathy. Most patients with oligoarthritis, in Western countries, have a form that is not observed in adults and is characterized by an early onset and the positivity of antinuclear antibodies (ANAs). RF− polyarthritis and psoriatic arthritis are still heterogeneous conditions. Undifferentiated arthritis is not a separate subset but includes those patients who do not fit in any category or fit in more than one. Recent clinical and laboratory observations have provided new
insights that strongly suggest that while some JIA categories identify definite disease entities, others still include heterogeneous conditions;4,5 JIA is therefore much more heterogeneous than RA. Second, with the exception of RF+ JIA, it is often difficult to predict, at disease onset, the longterm outcome of the disease6 and therefore, a careful evaluation during follow-up is required. Third, any therapy in children should be considered in relation to the developing body and prolonged life expectancy. Statural growth suppression is one of the several well-known corticosteroid side effects and has, of course, great relevance in pediatrics. It occurs in children who are receiving prolonged therapy in doses greater than 0.2–0.3 mg/kg/day of prednisone, increases with higher doses, and is almost universally seen when divided doses are used.7,8 However, wide interindividual variation exists in the severity of growth suppression and in the minimal dose required to suppress growth. Finally, it has to be mentioned that not all drugs that are available in adults are registered for use in children. Indeed, until recently, controlled trials in subjects at pediatric ages were rare. The situation has dramatically changed owing to the implementation by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)
doi: 10.1111/nyas.12436 C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1318 (2014) 65–70
65
Glucocorticoids in JIA
Malattia & Martini
Table 1. Frequency, age at onset, and sex distribution of the International League of Associations for Rheumatology (ILAR) categories of JIA
ILAR category
Frequency
Systemic arthritis Oligoarthritis Rheumatoid factor+ polyarthritis Rheumatoid factor− polyarthritis
5–15% 30–60% 3–7% 10–25%
Enthesitis-related arthritis Psoriatic arthritis
5–10% 3–10%
Undifferentiated arthritis
10–20%
Onset age Any pediatric age Early childhood Late childhood or adolescence Biphasic distribution; early peak 6 years Late childhood or adolescence Biphasic distribution; early peak 6 years –
Sex ratio F=M F >>> M F >> M F >> M M >> F F>M –
F, female; M, male.
of the “pediatric rule.” In brief, this rule states that if an industry wishes to register a new drug for a given disease, it has to provide data on safety and efficacy in children if an equivalent disease is also present at pediatric ages. Because of the pediatric rule, registrative trials for JIA have been performed for etanercept,9 adalimumab,10 abatacept,11 tocilizumab,12 and canakinumab.13 For the abovementioned reasons, in JIA corticosteroids have limited indications that will briefly be summarized. Intraarticular injections In a growing skeletal joint, contractures secondary to synovitis lead to deformity, as do joint contracture of the knee that causes a valgus deformity. Moreover, the unilateral involvement of the knee leads to a leg length discrepancy secondary to bone overgrowth on the affected side, likely in turn secondary to inflammation-induced hyperemia with release of growth factors. These anomalies that represented a major challenge in the past can now be effectively prevented by intraarticular steroid injections that induce a rapid relief of inflammation, restore function, and therefore interrupt the vicious circle leading to deformity.14 The long-acting steroid used worldwide is triamcinolone hexacetonide, which induces remissions that last much longer than those obtained with triamcinolone acetonide.15,16 The majority of patients show a remission of synovitis in the injected joint, lasting more than 6 months. However, for smaller joints or joints that are not easy to reach, the use of a more soluble corticosteroid drug is advisable.14 Imaging guidance (ultrasound) facilitates accurate placement of the needle within the 66
joint space, thus reducing the risk of side effects and maximizing the efficacy of the procedure. The most common adverse effect is subcutaneous atrophy at the site of injection, which is caused by delivery of the steroid preparation out of the joint space. This complication, which can usually be avoided with a careful injection technique, may resolve with time, although it can persist in some patients. The procedure can be performed in an ambulatory care setting, using local anesthesia with or without conscious sedation. Younger children or those who are candidates for multiple injections17 require general anesthesia. Chronic iridocyclitis Anterior uveitis, which involves the iris and the ciliary body (iridocyclitis), is a characteristic complication of JIA and occurs with much higher frequency in ANA+ patients.1,2 One or both eyes may be involved. The onset is insidious and often entirely asymptomatic, in contrast with the painful, acute iridocyclitis that is observed in spondyloarthropathies, such as enthesitis-related arthritis. Iridocyclitis usually occurs at the time of JIA diagnosis or thereafter, while it rarely precedes the onset of arthritis. The course may be relapsing or chronic and does not parallel the clinical course of arthritis. Because iridocyclitis is asymptomatic at onset, children with JIA should be screened periodically by slit-lamp examination. If the diagnosis is made early, topical steroids associated with mydiatrics are usually sufficient to control inflammation.18,19 Periocular subtenon injection of steroids are useful in cases where inflammation does not respond to topical
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therapy, and systemic steroids are indicated in case of ocular inflammation resistant to local treatments. Prednisolone is most commonly used at an induction dose of 1–2 mg/kg body weight, usually in a single morning dose that is then tapered on the basis of the clinical response. If systemic steroids fail to completely control ocular inflammation, immunosuppressants (particularly methotrexate (MTX)) and biologics (especially monoclonal antitumor necrosis factor (TNF-␣) antibodies) are indicated.18,19 It should be remembered that the long-term use of corticosteroids can cause cataracts and glaucoma. Corticosteroids as a bridge drug Experience with long-term low-dose prednisone, as in adult RA, is lacking in JIA. This is probably related to concerns about side effects, as well as to the difficulty of predicting long-term outcome at disease onset. Corticosteroids are used in severe polyarticular disease usually as a bridge drug. A short course of low-dose prednisone (0.5 mg/kg/day or less) is indeed indicated to alleviate pain and stiffness in patients with severe polyarthritis refractory to other therapies or while awaiting the full therapeutic effects of recently initiated MTX or biologic therapy. Corticosteroids are then progressively tapered and then suspended. This is now possible in the majority of patients owing particularly to the availability of biological agents, such as TNF-␣ blockers and abatacept. Multiple intraarticular injections with triamcinolone hexacetonide, with the same indications, may represent a valid alternative to the systemic administration of steroids. In a recently published study of a total of 220 patients who had 1096 joints injected, the cumulative probability of survival without synovitis flare was 50.0%, 31.5%, and 19.5% at 1, 2, and 3 years, respectively.17 Systemic JIA Systemic JIA (sJIA) has been, until recently, the main indication for long-term steroid therapy. As a consequence, this was also the disease in which the most severe side effects, ranging from permanent loss of stature to massive osteoporosis with extensive vertebral compression fractures, were more frequently observed. sJIA20,21 is characterized by the presence of a daily, high spiking fever, which is almost always associated with a salmon-colored evanescent,
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erythematous rash. Other extraarticular features include hepatomegaly and/or splenomegaly, generalized lymphoadenopathy, serositis (pericarditis and pleuritis), and laboratory abnormalities, such as neutrophilic leukocytosis, thrombocytosis, anemia, and elevated inflammatory markers. Systemic features of the disease may precede the onset of arthritis. The disease is observed at any pediatric age and affects children of both sexes with approximately equal frequency. It is considered the equivalent in children of adult-onset Still’s disease. The clinical course is highly variable; systemic features tend to recede during the initial months of the disease but may recur in case of disease relapse. About half of the patients eventually recover almost completely and usually with a good long-term prognosis. In the other half of the patients, the disease follows an unremitting course, with chronic arthritis representing the major long-term problem. The persistence of systemic features without arthritis is unusual. Markedly distinct clinical and laboratory features of sJIA suggest a different pathogenesis from the other forms of JIA. Prominent systemic features, a marked inflammatory response, an equal sex ratio, a lack of any association with human leukocyte antigen genes, and an absence of autoantibodies are all consistent with what is observed in autoinflammatory diseases.22 It is likely that sJIA is not a single disease but a syndrome that represents the terminal phase of different mechanisms all leading to a persistent activation of the innate immune system.5 Laboratory and clinical observations over the last 20 years have shown a major pathogenic role for interleukin (IL)-6 and IL-1 in sJIA and have laid the groundwork to implement new therapeutic strategies. In the 1990s, several laboratory studies23–26 led to the hypothesis that sJIA is an IL-6–driven disease.27 The major pathogenic role of IL-6 has been confirmed 10 years later by favorable results from a double-blind controlled study that demonstrated a marked efficacy of tocilizumab, a monoclonal antibody targeting the soluble IL-6 receptor in reducing systemic features and improving inflammatory arthritis in 56 patients with sJIA.28 More recently, the marked efficacy of tocilizumab has been confirmed compared to placebo in a controlled study performed in 112 patients with severe, persistent, and unresponsive sJIA.12
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The discovery of the important role of IL-1 in the etiopathogenesis of sJIA came from observation of the efficacy of the IL-1 receptor antagonist anakinra in the treatment of sJIA.29,30 The role of IL-1 is not in contradiction with the role of IL-6, because IL-1 is upstream to IL-6. Indeed, the use of such a drug in clinical practice has shown that the response to anakinra can identify two different subgroups of patients.31 One subgroup (accounting for approximately 40% of patients) with a dramatic response to IL-1 blockade (quite similar to that already observed in cryopyrinassociated autoinflammatory syndromes) is characterized by a prompt and complete normalization of clinical and laboratory features. The other subgroup has a resistant or incomplete response to anakinra, with a good response for systemic features but persistence of synovitis. The main differences observed between these two groups were in the number of joints involved and in neutrophils count; patients with fewer affected joints or with higher neutrophil counts had a high probability of responding to anti-IL-1 therapy. The therapeutic efficacy of anakinra has also been documented even in a controlled study.32 More recently, canakinumab, a monoclonal antibody against IL-1, proved to be effective in a dose-finding phase I/II trial33 and in a phase III trial in sJIA patients with active systemic features.13 These recent discoveries have radically changed the approach to the treatment of sJIA34 and have greatly reduced the need for long-term corticosteroid therapy. Indeed, both canakinumab and tocilizumab in many cases are sufficient to control the disease without the need for corticosteroids. From a practical point of view, during the diagnostic workup, patients are treated with nonsteroidal anti-inflammatory drugs. Once the diagnosis is made and if symptoms do not remit, as they typically do, steroid therapy is initiated (usually 2 mg/kg). If symptoms recur after a rapid steroid tapering, other therapies are indicated because the long-term use of steroids is associated with severe side effects. Different approaches are available to control the disease and reduce or withdraw steroids.35,36 If systemic symptoms no longer persist, treatment with MTX, anti-TNF-␣ agents, and abatacept can be indicated in sequence, although the results obtained with anti-TNF-␣ drugs have been less satisfactory in comparison with those observed 68
in the other forms of JIA (for abatacept there are still limited data).37 If systemic symptoms persist, either an anti-IL-1 or anti-IL-6 inhibitor is indicated. Usually, IL-1 inhibition is chosen as the first choice in patients in whom systemic features prevail over arthritis. As mentioned above, in many cases treatment is tapered and then corticosteroids are suspended. Recently, it has been suggested that early treatment with IL-1 inhibition could prevent the subsequent appearance of refractory arthritis in the large majority of patients. This hypothesis comes from observational studies and needs to be confirmed in prospective randomized trials.38,39 Macrophage activation syndrome For unknown reasons, children with sJIA are particularly susceptible to develop a life-threatening complication that occurs in around 6–8% of patients.40 This syndrome, called macrophage activation syndrome (MAS), is a form of reactive hemophagocytic lymphohistiocytosis and is characterized by sustained fever, pancytopenia, elevated transaminases and triglycerides, markedly increased ferritin concentrations, a coagulopathy with hemorrhagic manifestations, and neurologic symptoms. A bone marrow aspirate often shows the presence of phagocytosis of hematopoietic cells by macrophages. Specific criteria for the diagnosis of MAS in sJIA have been proposed and their validation process is ongoing.41,42 MAS is a medical emergency and should be promptly recognized and treated. Parenteral steroids in high divided doses in association with cyclosporine43,44 are usually able to control this complication if the diagnosis is prompt and the treatment rapidly instituted. Conclusions In conclusion, although the use of corticosteroids in JIA has been greatly reduced by the introduction of MTX and biological agents, there are clinical scenarios where it is still indicated. Intraarticular injections are essential in preventing deformities of the growing skeleton secondary to joint contracture. Multiple joint injections or systemic steroid can be used as a bridge drug to relieve symptoms in polyarticular disease while waiting for the effects of MTX and biologics. Furthermore, topical or systemic steroids are essential for the treatment of chronic anterior
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uveitis. Although systemic steroids keep their role in the treatment of sJIA, the advent of IL-1 and IL-6 blockers has greatly reduced their indication. Finally, steroids are essential, in combination with cyclosporine, in the therapy of MAS. Conflicts of interest
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17.
18.
The authors declare no conflicts of interest. 19.
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