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Idiopathic inflammatory myopathies: Definition and management of refractory disease
Autoimmunity Reviews 10 (2011) 720–724
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Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
Idiopathic inflammatory myopathies: Definition and management of refractory disease Mariana Brandão, António Marinho ⁎ Centro Hospitalar do Porto, Hospital de Santo António, Department of Medicine, Unidade de Imunologia Clínica, Largo do Professor Abel Salazar, no. 2, 4099-001 Porto, Portugal
a r t i c l e
i n f o
Available online 2 June 2011 Keywords: Refractory Myopathies Myositis Prognostic factors
a b s t r a c t Adult idiopathic inflammatory myopathies, commonly referred to as myositis, are a heterogeneous group of diseases with an autoimmune etiology. In this review, the authors are going to focus on myositis excluding inclusion body myositis. They will review the prognostic factors (for mortality and response to steroids), define refractory disease, introduce a new concept (presumed refractory disease), analyze definitions of active disease, damage and improvement criteria, and summarize therapeutic alternatives for refractory patients, based on different disease phenotypes. © 2011 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poor prognostic factors in idiopathic inflammatory myopathies . . . . . . . . . . . . . . . . . . . . . . Classification criteria and definition of refractory disease . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Should refractory myositis include patients who are presumed resistant to a first trial of steroids? . . 3.2. The concept is dynamic. When should we consider refractory disease after “standard immusuppresive 3.3. How should we measure response to therapy: disease activity and damage? . . . . . . . . . . . . 3.4. Definitions and exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Therapeutic approach of refractory disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. General management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Pharmacotherapy of patients with presumed refractory disease . . . . . . . . . . . . . . . . . . . 4.3. Management of patients with chronic refractory disease . . . . . . . . . . . . . . . . . . . . . . 5. Final comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Adult idiopathic inflammatory myopathies (IIMs), commonly referred to as myositis, are a heterogeneous group of diseases with an autoimmune etiology that share a number of features characterized by proximal muscle weakness and non-suppurative mononuclear cell inflammation of skeletal muscle [1,2]. There are five major types of IIMs: dermatomyositis (DM), polymyositis (PM), inclusion body myositis, autoimmune necrotizing myopathy and inflammatory myopathies associated with connective tissue
⁎ Corresponding author. Tel.: + 351 222077500; fax: + 351 222053218. E-mail addresses: [email protected] (M. Brandão), [email protected] (A. Marinho). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.05.021
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diseases (overlap myositis) [3]. In this review, the authors will focus on adult DM and PM, review the prognostic factors, define refractory disease and summarize therapeutic strategies based on different clinical phenotypes and presumed prognosis. This approach has several limitations, the main one being the absence of large cohorts of patients and randomized controlled trials, explained by the low annual incidence of these diseases: 2.2–7.7 cases/1,000,000 in adults [4]. 2. Poor prognostic factors in idiopathic inflammatory myopathies The recognition of the poor prognostic factors and the prediction of which patients are at risk for premature mortality can improve the initial management of the patients. In Table 1, the authors present
M. Brandão, A. Marinho / Autoimmunity Reviews 10 (2011) 720–724 Table 1 Predictors of poor outcome and causes of premature death. General characteristics at presentation of disease associated with poor prognosis Male sex Older age Proximal weakness Dysphagia Hypoventilation Interstitial lung disease Low serum creatine kinase levels Associated-cancer Presence of antisynthetase, anti-SRP and anti-155/140 autoantibodies Delay in diagnosis or treatment Principal causes of premature death Infection Cancer Cardiovascular disease Interstitial lung disease
some possible prognostic factors that can be crucial for therapeutic decisions. In the presentation of the disease there are some characteristics that, if positive, are associated with a poor outcome: male sex, older age, proximal weakness, dysphagia, hypoventilation, interstitial lung disease, and delay in diagnosis or treatment of the disease [5–7]. In contrast, a high creatine kinase (CK) level in the beginning of the disease seems to be protective, but more studies are necessary for confirmation [5,8]. The myositis autoantibodies can be myositis-specific, like the antisynthetase, the anti-signal recognition particle (anti-SRP) and the anti Mi-2 autoantibodies, or myositis-associated, for instance, antiPm-Scl, anti-U1 small nuclear ribonucleoprotein (anti-U1RNP), antiKu and anti-Ro/SSA autoantibodies [9]. Several studies have demonstrated that these autoantibodies can be helpful in the identification of patients with a poor outcome, for example: a) The antisynthetase autoantibodies (anti-Jo-1, anti-PL-7, anti-PL12, anti-OJ, anti-EJ, anti-KS and anti-Zo) identify a group of patients with a constellation of symptoms and signs known as the antisynthetase syndrome, which includes myositis, interstitial lung disease (ILD), nonerosive arthritis, fever and “mechanic's hands” (hyperkeratosis on the palmar or lateral surfaces of the fingers). The positivity of these autoantibodies is also a predictor of refractory disease with a polycyclic course resulting in worse prognosis [10–12]. In addition, some studies demonstrated that anti-Jo-1 antibody titers correlate with disease activity in an individual patient, particularly in the lung. [13]. b) The presence of anti-155/140 antibodies is strongly associated with malignancy in adults [14]; there is no sufficient data to establish if the presence of these antibodies is a sign of poor response to therapy [15]. c) Patients with anti-SRP antibodies usually have a more severe proximal and distal weakness (dysphagia is a prominent symptom), myalgias and cardiac involvement, appearing to be more resistant to steroid and immunosuppressive therapy [1,15,16]. d) There are also “good prognosis” autoantibodies; for example the presence of anti-Mi-2 antibodies is associated with a more important cutaneous disease, but patients usually have a low incidence of malignancy and a better response to steroid therapy [9,11,17]. Patients that are positive to the anti-PM/Scl, anti-U1snRNP and antiKu antibodies also respond well to steroids [15,18]. There are several causes of death in IIMs, and one of the most important is cancer. Regardless of the association with anti-155/140 seropositivity, patients with DM/PM have a greater risk of dying from cancer [5,19] and several predictive signs for development of cancer have been reported: cutaneous necrosis, low serum CK levels, increased serum erythrocyte sedimentation rate, decreased serum
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albumin level, poikiloderma, male gender and absence of arthralgia or interstitial lung disease [20–22]. Cancer can represent a paraneoplastic syndrome and be detected before or during the diagnosis of IIMs, but they also can be detected after. Usually, treatment of the underlying malignancy will improve myositis. The other two common causes of death are cardiovascular disease (particularly ischemic heart disease) and infection [5,23]. 3. Classification criteria and definition of refractory disease Idiopathic inflammatory myopathies are still classified by the Bohan and Peter's criteria (Table 2) [24,25], published in the New England Journal of Medicine in 1975, despite the efforts of different societies to achieve new criteria and validate tools to manage those diseases. However, Troyanov et al. [26] proposed a novel clinicoserological classification (Table 3) in which clinicians could analyze overlap features of connective tissue disease, associate antibodies and predict clinical course and response to prednisone. Defining refractory disease is challenging and we cannot be restrictive to the classical concept: disease not responding to therapy as expected. The authors' experience indicates that some clinical patterns of disease will benefit to be treated as refractory since the clinical presentation, for instance the anti-SRP autoantibodies seropositive adults patients who have a 5 year survival in less than 20% [16]. To address the refractory disease definition some key questions must be answered. 3.1. Should refractory myositis include patients who are presumed resistant to a first trial of steroids? The disease course can be classified as monocyclic, relapsing– remitting or chronic progressive [26]. The definition of first trial of steroids is heterogeneous, but an adequate initial trial can be defined as a daily methylprednisolone dose of at least 0.5 mg/kg for a month followed by a slow-down titration. Refractory myositis would be defined when this first therapy fails to induce remission after three months of treatment [27]. This classification allow us to include the concept of presumed resistance to a first trial of steroids (or presumed refractory disease), since there is enough data to assume that some clinical and pathological patterns almost always need immunosuppressive therapy; for example, chronic progressive course in anti-Jo-1 antibodies positive patients in contrast to common monocyclic pattern observed in those U1-RNP positive [28]. Patients with associated ILD (particularly the acute form presentation and the rare form of ILD with acute and rapidly progressive lung disease associated with clinically amyopathic dermatomyositis (CADM) and a novel anti-CADM-140 auto-antibody) [29–31], hypercapnic respiratory failure (hypoventilation) [32], proximal weakness at Table 2 Bohan and Peter criteria for the diagnosis of PM and DM. 1. Proximal muscle weakness: usually symmetrical 2. Elevated serum muscle enzymes: CK, aldolase 3. Electromyographic abnormalities: a) Common: myopathic potential–low amplitude, short duration and polyphasic action potentials b) Characteristic triad: (i) myopathic potentials; (ii) fibrillations, positive sharp waves, increased insertional activity; (iii) complex repetitive discharges 4. Muscle biopsy findings typical of PM or DM: necrosis, phagocytosis, regeneration, inflammation 5. Dermatological features of DM, Gottron's sign or papules, or heliotrope rash Definite DM requires four criteria (including rash) and definite PM requires four criteria (without rash). Probable disease comprises three criteria (including rash) for DM and three criteria (without rash) for PM. Possible disease requires two criteria (including rash) for DM and two criteria (without rash) for PM.
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Table 3 Novel clinicoserologic classification, from Troyanov et al. [26]. 1. Pure polymyositis 2. Pure dermatomyositis 3. Overlap myositis: with at least one clinical overlap feature and/or a myositis autoantibodya 4. Cancer-associated myositis: with clinical paraneoplasic features and without a myositis autoantibody or anti-Mi-2 a Antisynthethases (Jo-1, PL-7, PL-12, OJ, EJ, and KS), systemic sclerosis autoantibodies (centromere protein [CENP]-B, DNA topoisomerase I, RNA polymerase III, and Th/To), autoantibodies commonly associated with systemic sclerosis in overlap (U1RNP, U2RNP, U3RNP, U5RNP, PM-Scl, and Ku), anti-SRP (signal recognition particle), and antinucleoporins. Autoantibodies to Mi-2, Ro, and La are not included.
presentation (particularly in male, older and low serum CK patients) [33], cancer associated myositis [19] and acute deglutition problems [34], are not only related with poor prognosis but also with a probable resistance to steroid therapy. Despite open-label studies having proved that particular subgroups of patients would benefit from initial immunosuppressive therapy, based on better clinical and functional outcomes [35], we still cannot recommend this procedure in all presumed poor prognosis situations. With this approach, we can suggest the term presumed refractory disease in those patients we assume to have a chronic progressive or relapsing remitting course based on clinical and serological basis and consider, in selected cases, a more aggressive therapy, other than steroids. 3.2. The concept is dynamic. When should we consider refractory disease after “standard immusuppresive therapy”? There is no agreement about this issue. The authors propose to nominate refractory disease in IIMs patients that do not improve after at least one second-line immunosuppressive therapy or intravenous immunoglobulin (IVIg) therapy. 3.3. How should we measure response to therapy: disease activity and damage? The lack of consensus about disease activity and damage measures in IIMs patients inhibits the conduction and interpretation of clinical trials. A multispecialty group, called the International Myositis Assessment and Clinical Studies Group (IMACS) [36], has as purpose the validation of activity and damage indexes. Regarding the activity of the disease, a set of tools has been validated or partially validated for appliance in clinical trials and practice: physician global activity (Visual Analog Scale 10 cm), patient global activity (Visual Analog Scale 10 cm) [37], muscle strength testing (Manual Muscle Testing) [38], functional assessment tools (Health Assessment Questionnaire) [39], laboratorial measures (Serum Activity of Muscle Enzymes) [40], and extramuscular assessment (Myositis Disease Activity Assessment Tool) [41]. Clinical improvement can be defined as significant if there is a minimum of 15% of improvement for the domains of muscle strength and physical function, a minimum of 20% improvement for the physician and patient global assessments and extramuscular assessment, and a minimum of 30% of improvement for serum levels of muscle associated enzymes [42]. Damage is also a very difficult issue to evaluate in a single observation, but using a score like the Myositis Damage Index we can have a global and reliable assessment of damage in different organ systems [43]. All these partial validated tools can be found online in the IMACS site [36] and notwithstanding their common use in clinical trials, the author's opinion stands that, in rare diseases like IIMs, they also should be used in the clinical practice. These tools are useful to access clinical improvements, resistance to treatment and decide therapy.
3.4. Definitions and exclusion criteria In Table 4 we define definite refractory disease, presumed refractory disease and exclusion criteria. 4. Therapeutic approach of refractory disease 4.1. General management a) Confirmation of the correct diagnosis (take into consideration steroid myopathy and the utility of magnetic resonance imaging to distinguish or orientate a biopsy). b) Confirmation that the disease is refractory. c) Physical therapy. 4.2. Pharmacotherapy of patients with presumed refractory disease The definition of presumed refractory disease is described above. These patients have a high probability of requiring immunosuppressive therapy earlier in the natural history of the disease. The standard approach is to introduce immunosuppressive therapy only after the failure of a first trial of steroids [44]. The author's opinion is the introduction as soon as possible of methotrexate (7.5 mg/weekly to 30 mg/weekly oral or parental) or azathioprine (2.5 mg/kg/day) in this specific group of patients. This strategy enhances the possibility of “muscle sparing effect” and lower exposure to high doses of steroids, while it improves disease control [45]. However, there are some particular patients that justify a complementary approach: a) If the patient has acute deglutition problems or hypoventilation we propose intravenous bolus of methylprednisolone (1 g/day for three days) and IVIg (0.4 g/kg/day for 5 days or 1 g/day for 2 days) [46]. We also use IVIg (0.4 g/kg/day for 5 days or 1 g/day for 2 days) as maintenance for 3 to 6 months before a standard immunosuppressive therapy takes the full effect. b) Older and low serum CK patients with proximal weakness at presentation have a higher probability of steroid myopathy and poor functional outcome. The authors propose the induction with lower doses of prednisone (b20 mg/day) and, after normalization of CK, diminish the dose of steroids. We also propose the use of IVIg (0.4 g/kg/day for 5 days each month of a total of 3 months) and methotrexate or azathioprine. c) For patients with ILD (acute form) and antisynthetase antibodies, the use of methotrexate is not easy to recommend, given the difficulty to differentiate the pulmonary toxicity from activity of
Table 4 Definitions of refractory disease and exclusion criteria. Definite Fail to induce remission after an initial three months refractory disease adequate trial of steroid therapy, defined as a daily methylprednisolone dose of at least 0.5 mg/kg for a month, followed by a slow-down titration. IIMs that do not improve after at least one second line immunosuppressive therapy or intravenous immunoglobulin (IVIg) therapy (chronic refractory disease). Presumed Presence of bad prognosis antibodies refractory disease Interstitial lung disease (particularly acute form presentation) Proximal weakness at the presentation (particularly in male, older and low serum CK patients) Cancer associated myositis Hypoventilation and acute dysphagia Exclusion criteria Toxic myopathies Neurological disorders Metabolic disorders Muscle dystrophies Infections Mitochondrial disease
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the disease [47]. In literature, there are several combinations of drugs with the purpose of treating ILD. A classic approach of intravenous bolus of methylprednisolone (1 g for 3 days) and intravenous pulse of cyclophosphamide (0.5–1 g/m 2) monthly as initial approach is a possibility and probably the most tried first choice. The combination with cyclosporine or tacrolimus should be considered in refractory cases [48–51]. The association of mycophenolate mofetil (1–2 g/day) and cyclosporine (or tacrolimus) can also be an alternative [2]. Some studies consider cyclosporine as first choice in ILD [52,53]. Refractory patients should also be considered for biological therapy. The most attractive drug is rituximab (a monoclonal antibody against CD20+ B cells) with recent reports of cases demonstrating a good response and tolerability [54–56]. Despite alemtuzumab (anti-CD52) being also an attractive hypothesis, a higher number of infections are associated with this treatment [57]. d) If there is no lung disease in anti-Jo-1 positive patients, an initial treatment with high dose steroid therapy, IVIg and azathioprine (not methotrexate) should be considered. If patients seem to be refractory to this treatment, rituximab (375 mg/m2/weekly for 4 weeks) could be the most appropriate therapy. The authors' experience is that those patients are very difficult to be B-cells depleted and have a short time of depletion with frequent relapses. In those situations a maintenance therapy with rituximab (with or without cyclophosphamide) should be continued until a prolonged B cell depletion is achieved; probably it also achieves a prolonged remission (with lower maintenance doses of steroid therapy). e) Anti-SRP positive patients have probably (with some conflicting data in literature) the most severe form of IIMs, with the higher mortality rates. The approach could be similar to anti-Jo-1 positive patients [58], but an association with methotrexate and azathioprine should be considered before biological therapy. f) Cancer-related myositis has also a higher requirement of immunosuppressive therapy. Data are conflicting: some studies demonstrate a dramatic improvement after cancer therapy, other evidence shows a natural history without parallel cancer treatment. However, the successful treatment of the underlying malignant disease can improve the clinical course of the disease [19]. 4.3. Management of patients with chronic refractory disease Patients with chronic refractory disease have experienced a relapse–remitting course, with progressive functional impairment; they did not improve after at least one second-line immunosuppressive or IVIg therapy and never went treated as presumed refractory patients since the beginning. The approach should be the same as described above. Probably, if there is no contraindication, a more prolonged course of IVIg and an association of methotrexate and/or azathioprine is the best strategy to improve or delay progressive damage. Biological therapy should also be considered. Despite these considerations, chronic refractory patients will have a prolonged course of the disease, will be significantly disabled and will have a higher probability of infections and steroid myopathy; as so, they should be managed with low dose steroid therapy to avoid these complications. 5. Final comments There are no standard definitions of refractory disease that can be evaluated and tested in clinical trials to uniform treatments of refractory disease. The natural history of IIMs is not completely understood, as so, the therapeutic strategies should be adapted to each individual patient and his phenotypic and serological characteristics, as well as his functional status.
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Take-home messages • Definite refractory disease is as meaningful as presumed refractory disease. • It is essential to know the prognostic factors for mortality and treatment response. • The therapeutic strategies should be adapted to each individual patient and his phenotypic and serological characteristics as well as his functional status.
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[43] Rider LG, Lachenbruch PA, Monroe JB, Ravelli A, Cabalar I, Feldman BM, et al. For the IMACS Group, damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the myositis damage index. Arthritis Rheum 2009;60:3425–35. [44] Oddis CV. Idiopathic inflammatory myopathy: management and prognosis. Rheum Dis Clin Am 2002;28:979–1001. [45] Mastaglia FL, Zilko PJ. Inflammatory myopathies: how to treat the difficult cases. J Clin Neurosci 2003;10:99–101. [46] Marie I, Menard JF, Hatron PY, Hachulla E, Mouthon L, Tiev K, et al. Intravenous immunoglobulin's for steroid-refractory esophageal involvement related to polymyositis and dermatomyositis: a series of 37 patients. Arthritis Care Res (Hoboken) 2010;62:1748–55. [47] Lateef O, Shakoor N, Balk RA. Methotrexate pulmonary toxicity. Expert Opin Drug Saf 2005;4:723–30. [48] Tanaka F, Origuchi T, Migita K, Tominaga M, Kawakami A, Kawabe Y, et al. Successful combined therapy of cyclophosphamide and cyclosporine for acute exacerbated interstitial pneumonia associated with dermatomyositis. Intern Med 2000;39:428–30. [49] Kameda H, Nagasawa H, Ogawa H, Sekiguchi N, Takei H, Tokuhira M, et al. Combination therapy with corticosteroids, cyclosporine A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis. J Rheumatol 2005;32:1719–26. [50] Ochi S, Nanki T, Takada K, Suzuki F, Komano Y, Kubota T, et al. Favorable outcomes with tacrolimus in two patients with refractory interstitial lung disease associated with polymyositis/dermatomyositis. Clin Exp Rheumatol 2005;23:707–10. [51] Oddis CV, Sciurba FC, Elmagd KA, Starzl TE. Tacrolimus in refractory polymyositis with interstitial lung disease. Lancet 1999;353:1762–3. [52] Jankowska M, Butto B, Debska-Slizién A, Rutkowski B. Beneficial effect of treatment with cyclosporine A in a case of refractory antisynthetase syndrome. Rheumatol Int 2007;27:775–80. [53] Koreeda Y, Higashimoto I, Yamamoto M, Takahashi M, Kaji K, Fujimoto M, et al. Clinical and pathological findings of interstitial lung disease patients with antiaminoacyl-tRNA synthetase autoantibodies. Intern Med 2010;49:361–9. [54] Sem M, Molberg O, Lund MB, Gran JT. Rituximab treatment of the anti-synthetase syndrome: a retrospective case series. Rheumatology 2009;48:968–71. [55] Vandenbroucke E, Grutters JC, Altenburg J, Boersma WG, ter Borg EJ, van den Bosch JM. Rituximab in life threatening antisynthetase syndrome. Rheumatol Int 2009;29:1499–502. [56] majmudar S, Hall HA, Zimmermann B. Treatment of adult inflammatory myositis with rituximab: an emerging therapy for refractory patients. J Clin Rheumatol 2009;15:338–40. [57] Thompson B, Corris P, Miller JA, Cooper RG, Halsey JP, Isaacs JD. Alemtuzumab (Campath-1H) for treatment of refractory polymyosistis. J Rheumatol 2008;35: 2080–2. [58] Valiyil R, Casciola-Rosen L, Hong G, Mammen A, Christopher-Stine L. Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series. arthritis Care res (Hoboken) 2010;62:1328–34.
B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus Systemic lupus erythematosus and its preclinical lupus-prone mouse models are autoimmune disorders involving the production of pathogenic autoantibodies. Genetic predisposition to systemic lupus erythematosus results in B cell hyperactivity, survival of self-reactive B cells, and differentiation to autoantibody-secreting plasma cells (PCs). These corrupt B cell responses are, in part, controlled by excess levels of the cytokine BAFF that normally maintains B cell homeostasis and self-tolerance through limited production. B cell maturation Ag (BCMA) is a receptor for BAFF that, under nonautoimmune conditions, is important for sustaining enduring Ab protection by mediating survival of long-lived PCs but is not required for B cell maturation and homeostasis. Through analysis of two different lupus-prone mouse models deficient in BCMA, Jiang C, et al. (J Immunol 2011:186:6136–47) identified BCMA as an important factor in regulating peripheral B cell expansion, differentiation, and survival. We demonstrate that a BCMA deficiency combined with the lpr mutation or the murine lupus susceptibility locus Nba2 causes dramatic B cell and PC lymphoproliferation, accelerated autoantibody production, and early lethality. This study unexpectedly reveals that BCMA works to control B cell homeostasis and self-tolerance in systemic autoimmunity.
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Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
Idiopathic inflammatory myopathies: Definition and management of refractory disease Mariana Brandão, António Marinho ⁎ Centro Hospitalar do Porto, Hospital de Santo António, Department of Medicine, Unidade de Imunologia Clínica, Largo do Professor Abel Salazar, no. 2, 4099-001 Porto, Portugal
a r t i c l e
i n f o
Available online 2 June 2011 Keywords: Refractory Myopathies Myositis Prognostic factors
a b s t r a c t Adult idiopathic inflammatory myopathies, commonly referred to as myositis, are a heterogeneous group of diseases with an autoimmune etiology. In this review, the authors are going to focus on myositis excluding inclusion body myositis. They will review the prognostic factors (for mortality and response to steroids), define refractory disease, introduce a new concept (presumed refractory disease), analyze definitions of active disease, damage and improvement criteria, and summarize therapeutic alternatives for refractory patients, based on different disease phenotypes. © 2011 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poor prognostic factors in idiopathic inflammatory myopathies . . . . . . . . . . . . . . . . . . . . . . Classification criteria and definition of refractory disease . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Should refractory myositis include patients who are presumed resistant to a first trial of steroids? . . 3.2. The concept is dynamic. When should we consider refractory disease after “standard immusuppresive 3.3. How should we measure response to therapy: disease activity and damage? . . . . . . . . . . . . 3.4. Definitions and exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Therapeutic approach of refractory disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. General management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Pharmacotherapy of patients with presumed refractory disease . . . . . . . . . . . . . . . . . . . 4.3. Management of patients with chronic refractory disease . . . . . . . . . . . . . . . . . . . . . . 5. Final comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Adult idiopathic inflammatory myopathies (IIMs), commonly referred to as myositis, are a heterogeneous group of diseases with an autoimmune etiology that share a number of features characterized by proximal muscle weakness and non-suppurative mononuclear cell inflammation of skeletal muscle [1,2]. There are five major types of IIMs: dermatomyositis (DM), polymyositis (PM), inclusion body myositis, autoimmune necrotizing myopathy and inflammatory myopathies associated with connective tissue
⁎ Corresponding author. Tel.: + 351 222077500; fax: + 351 222053218. E-mail addresses: [email protected] (M. Brandão), [email protected] (A. Marinho). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.05.021
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diseases (overlap myositis) [3]. In this review, the authors will focus on adult DM and PM, review the prognostic factors, define refractory disease and summarize therapeutic strategies based on different clinical phenotypes and presumed prognosis. This approach has several limitations, the main one being the absence of large cohorts of patients and randomized controlled trials, explained by the low annual incidence of these diseases: 2.2–7.7 cases/1,000,000 in adults [4]. 2. Poor prognostic factors in idiopathic inflammatory myopathies The recognition of the poor prognostic factors and the prediction of which patients are at risk for premature mortality can improve the initial management of the patients. In Table 1, the authors present
M. Brandão, A. Marinho / Autoimmunity Reviews 10 (2011) 720–724 Table 1 Predictors of poor outcome and causes of premature death. General characteristics at presentation of disease associated with poor prognosis Male sex Older age Proximal weakness Dysphagia Hypoventilation Interstitial lung disease Low serum creatine kinase levels Associated-cancer Presence of antisynthetase, anti-SRP and anti-155/140 autoantibodies Delay in diagnosis or treatment Principal causes of premature death Infection Cancer Cardiovascular disease Interstitial lung disease
some possible prognostic factors that can be crucial for therapeutic decisions. In the presentation of the disease there are some characteristics that, if positive, are associated with a poor outcome: male sex, older age, proximal weakness, dysphagia, hypoventilation, interstitial lung disease, and delay in diagnosis or treatment of the disease [5–7]. In contrast, a high creatine kinase (CK) level in the beginning of the disease seems to be protective, but more studies are necessary for confirmation [5,8]. The myositis autoantibodies can be myositis-specific, like the antisynthetase, the anti-signal recognition particle (anti-SRP) and the anti Mi-2 autoantibodies, or myositis-associated, for instance, antiPm-Scl, anti-U1 small nuclear ribonucleoprotein (anti-U1RNP), antiKu and anti-Ro/SSA autoantibodies [9]. Several studies have demonstrated that these autoantibodies can be helpful in the identification of patients with a poor outcome, for example: a) The antisynthetase autoantibodies (anti-Jo-1, anti-PL-7, anti-PL12, anti-OJ, anti-EJ, anti-KS and anti-Zo) identify a group of patients with a constellation of symptoms and signs known as the antisynthetase syndrome, which includes myositis, interstitial lung disease (ILD), nonerosive arthritis, fever and “mechanic's hands” (hyperkeratosis on the palmar or lateral surfaces of the fingers). The positivity of these autoantibodies is also a predictor of refractory disease with a polycyclic course resulting in worse prognosis [10–12]. In addition, some studies demonstrated that anti-Jo-1 antibody titers correlate with disease activity in an individual patient, particularly in the lung. [13]. b) The presence of anti-155/140 antibodies is strongly associated with malignancy in adults [14]; there is no sufficient data to establish if the presence of these antibodies is a sign of poor response to therapy [15]. c) Patients with anti-SRP antibodies usually have a more severe proximal and distal weakness (dysphagia is a prominent symptom), myalgias and cardiac involvement, appearing to be more resistant to steroid and immunosuppressive therapy [1,15,16]. d) There are also “good prognosis” autoantibodies; for example the presence of anti-Mi-2 antibodies is associated with a more important cutaneous disease, but patients usually have a low incidence of malignancy and a better response to steroid therapy [9,11,17]. Patients that are positive to the anti-PM/Scl, anti-U1snRNP and antiKu antibodies also respond well to steroids [15,18]. There are several causes of death in IIMs, and one of the most important is cancer. Regardless of the association with anti-155/140 seropositivity, patients with DM/PM have a greater risk of dying from cancer [5,19] and several predictive signs for development of cancer have been reported: cutaneous necrosis, low serum CK levels, increased serum erythrocyte sedimentation rate, decreased serum
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albumin level, poikiloderma, male gender and absence of arthralgia or interstitial lung disease [20–22]. Cancer can represent a paraneoplastic syndrome and be detected before or during the diagnosis of IIMs, but they also can be detected after. Usually, treatment of the underlying malignancy will improve myositis. The other two common causes of death are cardiovascular disease (particularly ischemic heart disease) and infection [5,23]. 3. Classification criteria and definition of refractory disease Idiopathic inflammatory myopathies are still classified by the Bohan and Peter's criteria (Table 2) [24,25], published in the New England Journal of Medicine in 1975, despite the efforts of different societies to achieve new criteria and validate tools to manage those diseases. However, Troyanov et al. [26] proposed a novel clinicoserological classification (Table 3) in which clinicians could analyze overlap features of connective tissue disease, associate antibodies and predict clinical course and response to prednisone. Defining refractory disease is challenging and we cannot be restrictive to the classical concept: disease not responding to therapy as expected. The authors' experience indicates that some clinical patterns of disease will benefit to be treated as refractory since the clinical presentation, for instance the anti-SRP autoantibodies seropositive adults patients who have a 5 year survival in less than 20% [16]. To address the refractory disease definition some key questions must be answered. 3.1. Should refractory myositis include patients who are presumed resistant to a first trial of steroids? The disease course can be classified as monocyclic, relapsing– remitting or chronic progressive [26]. The definition of first trial of steroids is heterogeneous, but an adequate initial trial can be defined as a daily methylprednisolone dose of at least 0.5 mg/kg for a month followed by a slow-down titration. Refractory myositis would be defined when this first therapy fails to induce remission after three months of treatment [27]. This classification allow us to include the concept of presumed resistance to a first trial of steroids (or presumed refractory disease), since there is enough data to assume that some clinical and pathological patterns almost always need immunosuppressive therapy; for example, chronic progressive course in anti-Jo-1 antibodies positive patients in contrast to common monocyclic pattern observed in those U1-RNP positive [28]. Patients with associated ILD (particularly the acute form presentation and the rare form of ILD with acute and rapidly progressive lung disease associated with clinically amyopathic dermatomyositis (CADM) and a novel anti-CADM-140 auto-antibody) [29–31], hypercapnic respiratory failure (hypoventilation) [32], proximal weakness at Table 2 Bohan and Peter criteria for the diagnosis of PM and DM. 1. Proximal muscle weakness: usually symmetrical 2. Elevated serum muscle enzymes: CK, aldolase 3. Electromyographic abnormalities: a) Common: myopathic potential–low amplitude, short duration and polyphasic action potentials b) Characteristic triad: (i) myopathic potentials; (ii) fibrillations, positive sharp waves, increased insertional activity; (iii) complex repetitive discharges 4. Muscle biopsy findings typical of PM or DM: necrosis, phagocytosis, regeneration, inflammation 5. Dermatological features of DM, Gottron's sign or papules, or heliotrope rash Definite DM requires four criteria (including rash) and definite PM requires four criteria (without rash). Probable disease comprises three criteria (including rash) for DM and three criteria (without rash) for PM. Possible disease requires two criteria (including rash) for DM and two criteria (without rash) for PM.
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Table 3 Novel clinicoserologic classification, from Troyanov et al. [26]. 1. Pure polymyositis 2. Pure dermatomyositis 3. Overlap myositis: with at least one clinical overlap feature and/or a myositis autoantibodya 4. Cancer-associated myositis: with clinical paraneoplasic features and without a myositis autoantibody or anti-Mi-2 a Antisynthethases (Jo-1, PL-7, PL-12, OJ, EJ, and KS), systemic sclerosis autoantibodies (centromere protein [CENP]-B, DNA topoisomerase I, RNA polymerase III, and Th/To), autoantibodies commonly associated with systemic sclerosis in overlap (U1RNP, U2RNP, U3RNP, U5RNP, PM-Scl, and Ku), anti-SRP (signal recognition particle), and antinucleoporins. Autoantibodies to Mi-2, Ro, and La are not included.
presentation (particularly in male, older and low serum CK patients) [33], cancer associated myositis [19] and acute deglutition problems [34], are not only related with poor prognosis but also with a probable resistance to steroid therapy. Despite open-label studies having proved that particular subgroups of patients would benefit from initial immunosuppressive therapy, based on better clinical and functional outcomes [35], we still cannot recommend this procedure in all presumed poor prognosis situations. With this approach, we can suggest the term presumed refractory disease in those patients we assume to have a chronic progressive or relapsing remitting course based on clinical and serological basis and consider, in selected cases, a more aggressive therapy, other than steroids. 3.2. The concept is dynamic. When should we consider refractory disease after “standard immusuppresive therapy”? There is no agreement about this issue. The authors propose to nominate refractory disease in IIMs patients that do not improve after at least one second-line immunosuppressive therapy or intravenous immunoglobulin (IVIg) therapy. 3.3. How should we measure response to therapy: disease activity and damage? The lack of consensus about disease activity and damage measures in IIMs patients inhibits the conduction and interpretation of clinical trials. A multispecialty group, called the International Myositis Assessment and Clinical Studies Group (IMACS) [36], has as purpose the validation of activity and damage indexes. Regarding the activity of the disease, a set of tools has been validated or partially validated for appliance in clinical trials and practice: physician global activity (Visual Analog Scale 10 cm), patient global activity (Visual Analog Scale 10 cm) [37], muscle strength testing (Manual Muscle Testing) [38], functional assessment tools (Health Assessment Questionnaire) [39], laboratorial measures (Serum Activity of Muscle Enzymes) [40], and extramuscular assessment (Myositis Disease Activity Assessment Tool) [41]. Clinical improvement can be defined as significant if there is a minimum of 15% of improvement for the domains of muscle strength and physical function, a minimum of 20% improvement for the physician and patient global assessments and extramuscular assessment, and a minimum of 30% of improvement for serum levels of muscle associated enzymes [42]. Damage is also a very difficult issue to evaluate in a single observation, but using a score like the Myositis Damage Index we can have a global and reliable assessment of damage in different organ systems [43]. All these partial validated tools can be found online in the IMACS site [36] and notwithstanding their common use in clinical trials, the author's opinion stands that, in rare diseases like IIMs, they also should be used in the clinical practice. These tools are useful to access clinical improvements, resistance to treatment and decide therapy.
3.4. Definitions and exclusion criteria In Table 4 we define definite refractory disease, presumed refractory disease and exclusion criteria. 4. Therapeutic approach of refractory disease 4.1. General management a) Confirmation of the correct diagnosis (take into consideration steroid myopathy and the utility of magnetic resonance imaging to distinguish or orientate a biopsy). b) Confirmation that the disease is refractory. c) Physical therapy. 4.2. Pharmacotherapy of patients with presumed refractory disease The definition of presumed refractory disease is described above. These patients have a high probability of requiring immunosuppressive therapy earlier in the natural history of the disease. The standard approach is to introduce immunosuppressive therapy only after the failure of a first trial of steroids [44]. The author's opinion is the introduction as soon as possible of methotrexate (7.5 mg/weekly to 30 mg/weekly oral or parental) or azathioprine (2.5 mg/kg/day) in this specific group of patients. This strategy enhances the possibility of “muscle sparing effect” and lower exposure to high doses of steroids, while it improves disease control [45]. However, there are some particular patients that justify a complementary approach: a) If the patient has acute deglutition problems or hypoventilation we propose intravenous bolus of methylprednisolone (1 g/day for three days) and IVIg (0.4 g/kg/day for 5 days or 1 g/day for 2 days) [46]. We also use IVIg (0.4 g/kg/day for 5 days or 1 g/day for 2 days) as maintenance for 3 to 6 months before a standard immunosuppressive therapy takes the full effect. b) Older and low serum CK patients with proximal weakness at presentation have a higher probability of steroid myopathy and poor functional outcome. The authors propose the induction with lower doses of prednisone (b20 mg/day) and, after normalization of CK, diminish the dose of steroids. We also propose the use of IVIg (0.4 g/kg/day for 5 days each month of a total of 3 months) and methotrexate or azathioprine. c) For patients with ILD (acute form) and antisynthetase antibodies, the use of methotrexate is not easy to recommend, given the difficulty to differentiate the pulmonary toxicity from activity of
Table 4 Definitions of refractory disease and exclusion criteria. Definite Fail to induce remission after an initial three months refractory disease adequate trial of steroid therapy, defined as a daily methylprednisolone dose of at least 0.5 mg/kg for a month, followed by a slow-down titration. IIMs that do not improve after at least one second line immunosuppressive therapy or intravenous immunoglobulin (IVIg) therapy (chronic refractory disease). Presumed Presence of bad prognosis antibodies refractory disease Interstitial lung disease (particularly acute form presentation) Proximal weakness at the presentation (particularly in male, older and low serum CK patients) Cancer associated myositis Hypoventilation and acute dysphagia Exclusion criteria Toxic myopathies Neurological disorders Metabolic disorders Muscle dystrophies Infections Mitochondrial disease
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the disease [47]. In literature, there are several combinations of drugs with the purpose of treating ILD. A classic approach of intravenous bolus of methylprednisolone (1 g for 3 days) and intravenous pulse of cyclophosphamide (0.5–1 g/m 2) monthly as initial approach is a possibility and probably the most tried first choice. The combination with cyclosporine or tacrolimus should be considered in refractory cases [48–51]. The association of mycophenolate mofetil (1–2 g/day) and cyclosporine (or tacrolimus) can also be an alternative [2]. Some studies consider cyclosporine as first choice in ILD [52,53]. Refractory patients should also be considered for biological therapy. The most attractive drug is rituximab (a monoclonal antibody against CD20+ B cells) with recent reports of cases demonstrating a good response and tolerability [54–56]. Despite alemtuzumab (anti-CD52) being also an attractive hypothesis, a higher number of infections are associated with this treatment [57]. d) If there is no lung disease in anti-Jo-1 positive patients, an initial treatment with high dose steroid therapy, IVIg and azathioprine (not methotrexate) should be considered. If patients seem to be refractory to this treatment, rituximab (375 mg/m2/weekly for 4 weeks) could be the most appropriate therapy. The authors' experience is that those patients are very difficult to be B-cells depleted and have a short time of depletion with frequent relapses. In those situations a maintenance therapy with rituximab (with or without cyclophosphamide) should be continued until a prolonged B cell depletion is achieved; probably it also achieves a prolonged remission (with lower maintenance doses of steroid therapy). e) Anti-SRP positive patients have probably (with some conflicting data in literature) the most severe form of IIMs, with the higher mortality rates. The approach could be similar to anti-Jo-1 positive patients [58], but an association with methotrexate and azathioprine should be considered before biological therapy. f) Cancer-related myositis has also a higher requirement of immunosuppressive therapy. Data are conflicting: some studies demonstrate a dramatic improvement after cancer therapy, other evidence shows a natural history without parallel cancer treatment. However, the successful treatment of the underlying malignant disease can improve the clinical course of the disease [19]. 4.3. Management of patients with chronic refractory disease Patients with chronic refractory disease have experienced a relapse–remitting course, with progressive functional impairment; they did not improve after at least one second-line immunosuppressive or IVIg therapy and never went treated as presumed refractory patients since the beginning. The approach should be the same as described above. Probably, if there is no contraindication, a more prolonged course of IVIg and an association of methotrexate and/or azathioprine is the best strategy to improve or delay progressive damage. Biological therapy should also be considered. Despite these considerations, chronic refractory patients will have a prolonged course of the disease, will be significantly disabled and will have a higher probability of infections and steroid myopathy; as so, they should be managed with low dose steroid therapy to avoid these complications. 5. Final comments There are no standard definitions of refractory disease that can be evaluated and tested in clinical trials to uniform treatments of refractory disease. The natural history of IIMs is not completely understood, as so, the therapeutic strategies should be adapted to each individual patient and his phenotypic and serological characteristics, as well as his functional status.
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Take-home messages • Definite refractory disease is as meaningful as presumed refractory disease. • It is essential to know the prognostic factors for mortality and treatment response. • The therapeutic strategies should be adapted to each individual patient and his phenotypic and serological characteristics as well as his functional status.
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B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus Systemic lupus erythematosus and its preclinical lupus-prone mouse models are autoimmune disorders involving the production of pathogenic autoantibodies. Genetic predisposition to systemic lupus erythematosus results in B cell hyperactivity, survival of self-reactive B cells, and differentiation to autoantibody-secreting plasma cells (PCs). These corrupt B cell responses are, in part, controlled by excess levels of the cytokine BAFF that normally maintains B cell homeostasis and self-tolerance through limited production. B cell maturation Ag (BCMA) is a receptor for BAFF that, under nonautoimmune conditions, is important for sustaining enduring Ab protection by mediating survival of long-lived PCs but is not required for B cell maturation and homeostasis. Through analysis of two different lupus-prone mouse models deficient in BCMA, Jiang C, et al. (J Immunol 2011:186:6136–47) identified BCMA as an important factor in regulating peripheral B cell expansion, differentiation, and survival. We demonstrate that a BCMA deficiency combined with the lpr mutation or the murine lupus susceptibility locus Nba2 causes dramatic B cell and PC lymphoproliferation, accelerated autoantibody production, and early lethality. This study unexpectedly reveals that BCMA works to control B cell homeostasis and self-tolerance in systemic autoimmunity.