Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Idiopathic Inflammatory Myopathies: Current and Future Department of Neurology, University of Wuerzburg, Josef-Schneider-Strasse 11, Wuerzburg, 97080 Germany Summary: Idiopathic inflammatory myopathies (notably poly-
also used. There are no defined guidelines or best treatment myositis and dermatomyositis) a r e relatively uncommon dis- protocols agreed on internationally; therefore, the medical eases with a heterogeneous clinical presentation. Only a few approach must be individualized based on the severity of randomized, double-blind, placebo-controlled trials have clinical presentation, disease duration, presence of extra- been performed, measures to assess outcome and response to muscular features, and prior therapy and contraindications to treatment have to be validated. Initial treatment options of particular agents. Approximately 25% of patients are non- first choice are corticosteroids, although rarely tested in responders and continue to experience clinical relapses.
randomized, controlled trials. Unfortunately, not all patients Those are candidates for alternative treatment options and respond to them and many develop undesirable side effects.
Thus, second line agents or immunosuppressants given in New immunoselective therapies directed toward cytokine combination with corticosteroids are used. For dermatomy- modulation, immune cell migration, or modification of certain ositis/polymyositis, combination with azathioprine is most immune subsets (B- and T-cells) are a promising avenue of common. In case this combination is not sufficient or appli- research and clinical application. Possible future therapeutic cable, intravenous immunoglobulins are justified. Alterna- options are presented and discussed. Key Words: Idiopathic
tive or stronger immunosuppressants, such as cyclosporine inflammatory myopathies, myositis, therapy, polymyositis, der- A, cyclophosphamide, methotrexate, or mycophenolate are matomyositis, inclusion body myositis.
around 1/100,000 (DM Ͼ IBM Ͼ PM). The key symp-tom of all three forms is muscle weakness, whereas Myositis is the generic term for a relatively rare, het- sensibility and tendon reflexes are normally maintained.
erogeneous group of acquired inflammatory muscle dis- Although distribution of muscle weakness has a proxi- eases that can lead to progressive restriction of mobility, mal-symmetrical pattern in PM/DM, IBM also occurs in as well as increase in morbidity, due to involvement of distal muscle groups, especially foot extensors and finger extramuscular organs. Treatment of inflammatory mus- flexors. Distribution can be asymmetrical (reviewed in cle diseases is challenging and can become extremely Myositis is classified according to clinical, histologi- Up to 50% of patients have pain in muscles and/or cal, and immune-pathological criteria. The key compo- hinges. All three forms may be associated with dyspha- nents of myositis diagnosis entail assessment of clinical gia, an effect of the respiratory and neck muscles. In PM features, serological tests, electromyography, and muscle and DM, even the heart may be affected, as seen by biopsy changes Imaging procedures can aid to changes in electrocardiographic measurements, pericar- the diagnosis. Incidence of the three idiopathic inflam- ditis, dilatative cardiomyopathy, and/or coronary failure, matory myopathies, polymyositis (PM), dermatomyositis and the lungs may be affected as evidenced by interstitial (DM), and inclusion body myositis (IBM), together is lung disease. In DM, characteristic skin alterations occurin children sometimes, developing calcifications.
Recent studies with stricter application of histopatho- Address correspondence and reprint requests to: Heinz Wiendl, MD, logical diagnostic criteria show that polymyositis occurs Department of Neurology, University of Wuerzburg, Josef-Schneider- far more seldom than had been claimed in earlier studies, Strasse 11, Wuerzburg, 97080 Germany. E-mail: making PM the rarest entity within all forms of idio- Vol. 5, 548 –557, October 2008 The American Society for Experimental NeuroTherapeutics, Inc.
Table 1. Clinical and Diagnostic Characteristics of PM, DM, and IBM
CK ϭ creatine kinase; DM ϭ dermatomyositis; EMG ϭ electromyography; IBM ϭ inclusion body myositis; PM ϭ polymyositis.
pathic Inclusion body myositis is the most merely unknown so far (reviewed in Chevrel et frequent inflammatory myopathy in patients over age 50, ranging slightly behind dermatomyositis with regard to In IBM, a degenerative process with accumulation of frequency of all ages. Various groups have proposed pathological protein fibrils, similar to the process in Alz- revised diagnostic criteria for idiopathic myositis, espe- heimer’s disease, is currently The trigger is cially to enable a better standardization and validation of unknown. It is assumed that this trigger initiates a cas- clinical trials and trial endpoints. This is particularly the cade of degenerative and inflammatory events, including merit of the International Myositis Assessment and Clin- amyloid deposits, oxidative stress, abnormal signal trans- duction, and immune reaction (reviewed in Muscle MRI can be very useful in diagnosing and assessing activity in patients with myositis because of its The prognosis for myositis has improved over the past sensitivity on measuring the tissue’s water content. Mus- years. In the absence of malignity, the 5-year survival cle edema, as detected by MRI, correlates well with rates of adults with DM or PM is between 70% to 89%, inflammatory changes. A comparison of the T1- and according to literature sources (e.g., Engel et and T2-weighted fat suppressed sequences is used to inter- Airio et A retrospective study analyzed the disease pret whether weakness is attributable to ongoing inflam- mation (sometimes patchy), a mixed picture of both in- pressive therapy, 40% of patients showed remission; a flammation and damage, or muscle atrophy with fat further 43% of patients showed improvement; and in 17%, the clinical symptoms exacerbated. Survival rates The cause of PM, DM, and IBM is unknown thus were about 83% after 1 year, 77% after 5 years. Among While in PM, a T cell-mediated autoimmune pro- the causes of death were malignoma (47%) and pulmo- cess is assumed, the cause of DM is assumed to be driven nary complications (35%). Prognosis of paraneoplastic myositis is essentially determined by the underlying ma- antigen(s) directed against the immune reactions are lignant disease. Otherwise, poor prognostic factors that Neurotherapeutics, Vol. 5, No. 4, 2008 are common to several studies include old age, nonwhite validation and studies on its reliability are also being race, bulbar involvement, delayed treatment, and cardio- CURRENT THERAPY
Therapy of DM/PM
Pragmatically, therapy of myositis can be divided into The main objective of treatment is to improve muscle three phases: 1) initial therapy, 2) maintenance therapy, strength and to obtain remission, or at least clinical sta- bilization. Muscle strength, and clinical and laboratory Phase 1: Initial therapy.
criteria should be routinely assessed. Consensus about of first choice in DM, as well as in PM. Acute therapy the assessment of disease activity confirms that several usually starts with 1 to 2 mg/kg body weight for 2 to 4 domains must be considered, namely: 1) global disease weeks, followed by a slow dose reduction, and finally an activity, by which some use patient/parent visual ana- alternating administration every other day. Most patients logue scales; 2) muscle strength, by using manual muscle initially respond very positively. However, as the steroid testing; 3) physical function, by using the Health Assess- doses are reduced in the course of therapy (and with it the ment Questionnaire/Childhood Health Assessment Ques- adverse effects), additional administration of an immune tionnaire; 4) laboratory evaluation, by measuring at least suppressant becomes necessary in many cases, especially two serum enzymes from creatine kinase, aldolase, lac- in cases with more severe affection. In the case of pro- tatdehydrogenase, aspartate aminotransferase, or alanine nounced muscular symptoms, some authors recommend aminotransferase; and 5) by determining extra-skeletal an initial high-dose steroid therapy (summary, Immunosuppressants are used for long-term therapy; a Extended set measures can be added to each of these low-dose corticosteroid therapy, partly in combination five domains to achieve greater accuracy, including dy- with azathioprine, is often required for 1 to 3 years as namometry, maximum voluntary isometric contraction, and MRI (e.g., T2-weighted images, muscle biopsies, which in principle existed for decades, are mostly em- cutaneous assessment tools, and so forth).
pirical or based on smaller therapeutical trials. There As the patients’ own perception of their quality of life have not been any larger randomized, placebo-con- is also important, it may be assessed by the 36-item short trolled, therapeutic studies so far.
Disease damage remains difficult to assess and a Azathioprine, given in dosages up to 3 mg/kg body suitable index to agree and to be validated is awaited. An weight, is often initiated early in the disease course, international consensus on disease activity and damage, particularly in patients with a more severe disease course partially validated, has just been published by the (e.g., in patients with general weakness, respiratory im- IMACS In assessing disease activity, two indi- pairment, or dysphagia). The delay of 3 to 6 months until ces were tested: 1) myositis intention to treat index, onset of clinical efficacy has to be considered. Combi- which consists of a modification of the British Isles nation of corticosteroids with azathioprine is the most Lupus Assessment Group and is based on the principle of common combination in PM/DM therapy.
the physician’s intention to treat, and 2) myositis disease Methotrexat, a folic acid antagonist, given in a dose of activity assessment visual analogue scale, by a series of 7.5 to 25 mg/week, operates faster than azathioprine, but 10-cm video-assisted surgeries completed by the physi- has a higher toxicity level. One adverse effect may be cian to assess the patient in systems that may be affected pneumonitis, which might sometimes be difficult to dis- in myositis. Both show initially good results, but with tinguish from interstitial lung impairment (e.g., in JO-1 certain limitations and further need for validation. For syndrome). Therapy should start with the administra- the assessment of myositis-induced damage, a myositis tion of 7.5 mg once a week orally. After 3 weeks, the damage index has been suggested. This index evaluates dose may be raised by 2.5 mg/week up to a target dose the extent and severity of damage in the different organs of 10 to 25 mg/week, depending on the clinical symp- that might be affected, using modification of the Sys- toms. A maximum dose of 25 mg/week should not be temic Lupus International Collaborative Clinics/Ameri- can College of Rheumatology (SLICC/ACR) damage Cyclosporine in a dose of 2.5 to 5 mg/kg body weight, administered in two doses, depending on plasma level In addition, the myositis damage score (MYODAM) and efficacy, can also be used. Cyclosporine inhibits index has been developed. In this index, a myositis dam- T-cell activation and is well known in the therapy of age score, represented by a series of 10-cm video-as- transplant rejection. The regimen used in myositis re- sisted surgeries, is used to quantify the severity of dam- quires good compliance of the patient, as well as reg- age in the various organs affected. However, a formal ular controls of serum level and renal function, be- Neurotherapeutics, Vol. 5, No. 4, 2008 Table 2. Pragmatic Therapy of Myositis: PM/DM
by 5–10 mg of daily dose and/orafter “alternate day program” Maintenance dose:5–10 mg/day or 20 mg every other (corresponding to plasma level andefficacy) weight). Plasma level (“throughlevel”): 1–2 mg/L Repeat after 6–9 months or afterclinical response Repeat after 6–9 months and/orafter clinical response Alternative treatment options or individual treatment options (e.g., rituximab, tumor necrosis factor-alpha receptor- antagonists, tacrolimus/FK507, alemtuzumab) 1 ϭ recommendation is based on at least one adequate, valid clinical study (e.g., randomized); ↔ ϭ no valid and clinical studies or safeevidences are available; i.v. ϭ intravenous; p.o. ϭ per os; DM ϭ dermatomyositis; IBM ϭ inclusion body myositis; PM ϭ polymyositis.
cause cyclosporine shows variable resorption and a nolate mofetil (2 g/day) (e.g., Majithia and Harisdan- dose-related nephrotoxicity. The latter occurs in most cases only in doses from 5 to 6 mg/kg body weight/ This substance selectively blocks the purine synthesis in day. Existing kidney diseases and arterial hypertonus lymphocytes, and thus inhibits their proliferation. The increase the risk of a renal impairment triggered by most important side effects of mycophenolate mofetil include chronic diarrhea, hemolytic anemia and edema.
Administration of cyclophosphamide (1 to 2 mg/kg Mycophenolate mofetil is an option when azathioprine body weight/d orally, 0.0 to 1.0 g/m2 i.v.) in DM/PM is fails and is increasingly preferred to azathioprine in only necessary when common therapy has failed, or in transplantation medicine. Recently, increasing numbers the case of anti-synthethase syndromes with secondary of malformations were registered in pregnant patients with kidney transplants and preceding mycophenolate treatment of therapy-refractory myositis with mycophe- mofetil treatment during pregnancy. However, individual Neurotherapeutics, Vol. 5, No. 4, 2008 cases of progressive multifocal leukoencephalopathy From experience, problems during therapy occur when (PML) have been observed in immune-suppressed pa- many different substances have been used, but none of tients (lupus erythematodes). One case of a primary CNS them has been administered long enough or in appropri- lymphoma under mycophenolate mofetil therapy has ate doses. Attenuation of the known side effects of a long-term corticoid therapy, such as osteoporosis, and Intravenous immunoglobulins in patients not respond- gastric ulcera, can be achieved by giving antazida, proton ing to corticosteroids/azathioprine, therapy with intrave- pump inhibitors, and by substitution of calcium and vi- nous immunoglobulins (IVIG, 2g/kg body weight every 1 to 2 months) is justified. Convincing beneficial effectsof IVIG therapy have especially been shown for Therapy of sporadic IBM
In juvenile DM, immunoglobulins are often administered So far, sporadic inclusion body myositis (sIBM) has very early to prevent immunosuppressive strategies with proven to be relatively refractory to therapy. Corticoste- potentially numerous side effects, but the success is not roids and immunosuppressants have (with few excep- Also in therapy-resistant PM, cases of suc- tions) proven to be ineffective. However, no controlled cessful treatment with immunoglobulins have been pub- trials, neither about efficacy of corticosteroids or about However, these results are too inconsistent to efficacy comparison of the various immunosuppressive allow IVIG as a recommendation for primary therapy substances, exist in sIBM. Overall, response of sIBM to immunosuppressive therapy has been discussed very Phase 2: Maintenance therapy.
controversially. Until today, only a few authors consider pends on initial treatment response, but data shows that an immunotherapeutic treatment (i.e., corticosteroids after approximately 6 months, corticosteroid doses plus azathioprine or methotrexate) attempted over 3 to 6 should be reduced below “Cushing level.” An alternating months as justified (e.g., Mastaglia and administration is preferred (every other day). If after 3 Numerous negative or minimally encouraging trial re- months, the steroid dose is still clearly above the Cushing ports exist for immunomodulatory and/or immunosup- level and further reduction does not seem possible with- pressive strategies of sIBM. Examples include contro- out the risk of a relapse, immunosuppressants (see pre- viously mentioned) should be given in addi- tion. The first choice agent here is azathioprine. In childhood DM, however, methotrexate is preferred to A placebo-controlled pilot study over 12 months with anti-thymocyte globuline (ATG-Fresenius, Fresenius Phase 3: Long-term therapy.
AG, Bad Homburg, Germany) and methotrexate in 10 ical stabilization, low-dose, long-term therapy is nor- patients showed a constant muscular strength in the anti- mally necessary. In most cases, this is given as a com- thymocyte globuline/methotrexate group compared with bination of a corticosteroid and an immunosuppressant.
an exacerbation of 15% in the placebo group. There were For relapse prophylaxis, this medication is given for 1 to no severe side effects. The authors proposed application 3 years, and even longer, where appropriate. Duringlong-term therapy with corticosteroids, a reappearance of of this regimen in “young” IBM patients who show a muscle weakness might occur when creatine kinase ac- tivity is normal or unchanged, and this is possibly the Therapeutic benefit of repetitive immune adsorption occurrence of a steroid myopathy. Sometimes this might has been described in a patient with sIBM and monoclo- be hard to distinguish from the initial myositis symp- toms. In addition, symptoms are aggravated by immobi- apeutic option if there are immunological disturbances lization and accompanying systemic disease. In such cases, reduction of corticosteroids should be considered A controlled pilot study with 19 sIBM patients with under careful clinical observation. An increase in creat- oxandrolon (Oxandrin, Savient Pharmaceuticals, Inc., ine kinase activity and pathological spontaneous activity East Brunswick, NJ), a synthetic androgen, showed, in the electromyography are indicators voting against at best, a marginal effect with regard to muscular steroid myopathy. If clinical decision is ambiguous, a re-biopsy should be conducted. However, steroid myop- Alemtuzumab (Campath-1), a monoclonal antibody, is athy is rather improbable if there are no other signs of directed against CD52, a cell surface molecule present on iatrogenic Cushing symptoms, such as osteoporosis, various immune cells (particularly T cells, B cells, and cushingoid phenotype. Furthermore, it is important to dendritic cells) and inducing selective immune depletion distinguish between existing inflammatory disease activ- after intravenous application. Alemtuzumab was used in ity and residual disease after active DM/PM (“burned out a controlled study in patients with sIBM. Clinically, this immunoselective treatment showed no significant effects Neurotherapeutics, Vol. 5, No. 4, 2008 Table 3. Myositis: Synopsis of Most Important Treatment Recommendations
The idiopathic myositis syndromes consist of polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body A causal therapy of the dysimmune/idiopathic myositis syndromes is not established.
Therapeutic regimens are mostly empirical or are based on smaller therapeutic studies
Therapy of PM/DM:
PM and DM can be controlled with immunosuppressive therapy in the majority of cases.
For initial therapy, corticosteroids are the drug of first choice.
For long-term therapy, a low-dose corticosteroid therapy is often needed, partly in combination with immunosuppressive
therapy with azathioprine. Relapse prophylaxis is needed for 1 to 3 years or longer.
For patients that do not respond to corticosteroids/azathioprine, a treatment with intravenous immunoglobulins is justified.
Stronger immunosuppressive treatment regimens are used in patients with severe extramuscular organ manifestation.
Newer immunoselective therapies can be successful in cases of refractory disease. One option is immunoselective, B-cell directed treatment with anti-CD20 antibody rituximab. Treatment with rituximab can help to reduce concomitantimmunotherapies. Antibodies possibly associated with myositis syndromes neither predict nor correlate necessarily withthe therapeutic response to anti-CD20 treatment.
Treatment of Sporadic IBM:
sIBM is often characterized by a progressive disease course and therapeutic resistance.
Some authors recommend an initial treatment trial with monthly intravenous immunoglobulins, which can induce
A short-term (approximately 6 months) immunsuppressive treatment attempt can be considered in analogy to the therapy General Remark:
Regular control of muscular strength is needed to judge treatment response and necessary adaptation of
Laboratory Measures:Especially creatine kinase can be used as individual marker of treatment response.
In IBM, creatine kinase can be lowered without any clinical relevance.
on muscle strength, but the inflammatory infiltrations in RECENT REPORTS, ONGOING STUDIES AND
For IVIG, controversial reports exist. Dalakas et IDIOPATHIC INFLAMMATORY MYOPATHIES
could prove a significant improvement of dysphagia in a A number of novel therapies are currently being in- controlled study with 10 sIBM patients. In six patients, vestigated in clinical trials. Furthermore, numerous but not in the whole treatment group, there was a func- smaller series have provided preliminary evidence of tional recovery with regard to muscle strength and ev- potential use of certain substances in the treatment of eryday activities.In a double-blind, placebo-controlledstudy, a significant improvement of daily activities by 11% with constant muscle strength could be achieved in Mycophenolate mofetil has been promoted as a help- 22 sIBM patients in the course of 1 In contrast, ful immunosuppressive agent in the therapy of treatment- combination of steroids with IVIG did not show any refractory myositis (PM/DM). Seven patients have been efficacy in a controlled study in 36 sIBM reported by Majithia and Harisdangkul in An- Depending on the individual disease course, a thera- other six patients have been reported by Pisoni et in peutic attempt with IVIG over 6 months appears reason- 2007. As previously indicated, the risk of opportunistic able. After 6 months, therapeutic success should be clin- infection seems increased in combination with cortico- ically evaluated by improvement, stabilization, or further progression, and also evaluated electrophysiologically Three tumor necrosis factor-alpha (TNF-alpha) inhib- (e.g., decrease in pathological spontaneous activity) to be itors (infliximab, adalimumab, and entanercept), which able to provide a valuable basis for the decision on are approved for therapy of rheumatoid arthritis and/or psoriasis arthritis, ankylosing spondylosis, or inflamma- summarizes the most important therapeutic tory bowel disease, are currently being tested in DM and recommendations and “take home” remarks for the ther- PM. Etanercept was applied in 9 patients with IBM, and apy of DM/PM as well as sIBM. With regard to treat- after 6 and 12 months, there was no effect seen in com- ment recommendations and levels of evidence, it should be kept in mind that many studies are based on only very Myositis with interstitial lung disease plus concomitant positivity of aminoacyl transfer RNA synthetase antibodies Neurotherapeutics, Vol. 5, No. 4, 2008 (especially JO1) seem to respond positively to calcineurin FUTURE THERAPEUTIC AVENUES
The monoclonal antibody anti-CD52 (alemtuzumab, Albeit a significant number of patients with inflamma- CAMPATH-1) has been applied in a controlled study in tory muscle disease respond adequately to treatment with patients with sporadic IBM. Clinically, these immune- corticosteroids and immunosuppressive or modulatory selective treatments did not show significant positive agents, investigations continue for more effective drugs effects on muscle strength; however, inflammatory infil- with fewer side effects. Furthermore, recent findings elu- trates in muscles (seen in repetitive biopsies) were re- cidating the immunopathogenesis open new avenues for therapeutic targets or strategies (e.g., and Recent studies point to an important role for B cells and antibodies in the pathogenesis of dermatomyositis, One could formally separate those as approaches of: 1) but less so in polymyositis and inclusion body myositis general immunosuppression or immunomodulation, 2) immune-specific intervention, and 3) individualized ther- tibody directed against CD20 expressed on B cells (anti- apy (immune-specific intervention based on individual CD20), has already been used in a number of smaller pathogenic mechanisms encountered in one patient).
case series as well as open observations. The success of The first category (immunosuppressive or immuno- modulatory interventions) assumes that the immune sys- tem plays a key role in the pathogenesis of PM/DM/IBM.
Therefore, agents with immunosuppressive or immuno- modulatory properties, but with a beneficial side effect suggest that rituximab may be effective in the profile, are attractive for studies in myositis. This would treatment of refractory polymyositis. A positive thera- include a number of already approved FDA (FDA) drugs peutic response of myositis associated with lung disease with indications in other autoimmune diseases, but thus (i.e., interstitial lung disease) and concomitant anti-ami- far is not reported as used off-label or in trials for in- noacyl transfer RNA synthetase antibodies (especially flammatory myopathies. With sufficient interest, clinical anti-JO1) was observed by Lambotte et as published trials of such drugs could advance rapidly. Such ap- in their report in 2005. Rituximab also has potential in proaches would not be considered as a causal treatment, the treatment of both myositis-specific auto-antibody- but might offer substances with a better risk-benefit pro- positive and -negative juvenile dermatomyositis, accord- file, potentially achieving higher rates of remissions, es- ing to results from a case series (n ϭ 4) of pediatric pecially in the inflammatory myopathies PM/DM.
For adult patients with dermatomyositis, evi- The second category would be interventions that are dence of efficacy is mixed. Findings from case immunoselective. This is certainly a very attractive and a case and an open-label pilot study (n ϭ promising area of research, assuming that key pathways suggest that rituximab can markedly improve the mus- or molecules or immune subsets involved in the patho-genesis of DM versus PM versus IBM could be selec- culoskeletal and cutaneous symptoms of the disease; in contrast, results from another open-label pilot studies Pathogenetic models that assume that T cells injure (n ϭ suggest that rituximab has limited effect on the muscle fibers in polymyositis and inclusion body myo- skin. Titers of antibodies associated with these syn- sitis promote agents or strategies to affect T-cell func- dromes (e.g., anti-Jo) do not necessarily predict or cor- tion. New biologic agents targeting T-cell activation, relate with the clinical response to rituximab. This inter- transmigration and antigen recognition may be reward- esting and important therapeutic strategy is currently ing. Such immunoselective or semi-specific immunother- being tested in an NIH-supported trial in therapy-refractory apies could be accomplished with biotechnologicals di- rected against co-stimulatory molecules (e.g., CD28, CTLA-4, inducible costimulatory signal ligand/induc- Of note, therapies with monoclonal antibodies have ible costimulatory signal pathway, B7-H1/PD-1 path- been associated with severe adverse effects. Specifically, way), adhesion molecules (e.g., integrins/lymphocyte the potential risk of opportunistic infections (e.g., pro- function associated antigen-1/intercellular adhesion mol- gressive multifocal leukoencephalopathy occurred in as- ecule), immune cell subpopulations (e.g. CD52, alemtu- sociation with anti-CD20 treatment) or the occurrence of zumab), certain cytokines (e.g., tumor necrosis factor- life-threatening autoimmune disorders (idiopathic throm- alpha, interleukin-6) or T-cell receptor-induced pathways bocytopenic purpura, idiopathic thrombocytopenic pur- pura, occurred in association with anti-CD52, alemtu- approved FDA drugs for the treatment of psoriasis.
zumab) should serve as a note of caution.
Neurotherapeutics, Vol. 5, No. 4, 2008 rheumathoid arthritis with efficacy also in psoriasis.
upregulation of T-regulatory cells (quantitatively or These drugs were all designed to disrupt interaction of T qualitatively). These treatment attempts are of consider- cells with other cells. Efalizumab interferes with T-cell able interest also in other autoimmune disorders, includ- adhesion both to keratinocytes and endothelium via tar- geting CD11a. Furthermore, it disrupts the T-cell inter- Finally, the ideal therapy for myositis would be tai- action with dendritic cells and blocks the cutaneous entry lored for the individual driving pathogenetic mechanism of memory cytotoxic T All functions make its (see category 3 as previously mentioned). Such highly potential feasibility plausible in myositis. Alefacept tar- individualized therapy would take into account the dis- gets cells with high expression of CD2, to which LFA-3 ease entity and the driving pathogenetic mechanisms in binds. Alefacept is a fusion protein made from lympho- relation to the status of the disease. They could include cyte function-associated antigen-3 Abatacept antigen-specific therapies or consider relevant key mo- inhibits the T-cell surface molecule CD28 and its inter- lecular targets, and deduced from this, the application of action with the most important co-stimulatory ligand appropriate treatment or treatment combinations. Al- CD80 and CD86, expressed on all professional antigen- though this is certainly one of the “holy grails” or presenting cells, including dendritic cells and B cells.
“dreams” of any immune therapy of autoimmune disor- This CTLA-4 IG is an interesting example of how to ders, the possibilities and realistic chances to do so in bridge basic immunology with clinical application, al- idiopathic inflammatory myopathies are pretty far- ready successfully pursued in rheumatoid arthritis and fetched. Specifically in myositis, the driving antigen or psoriasis. Whether this substance (abatacept) or a similar antigens are merely unknown. However, one could as- sume to figure out the key pathogenetic elements based the treatment of myositis remains to be shown in the on gene array or chip analysis from muscle biopsy spec- imens in addition to peripheral blood. This approach had The interferon-alpha/beta pathway and its particular already elegantly shown the differences between the three key clinical entities IBM, PM, and and could couraged thoughts to target this pathway in clinical sit- theoretically also be a helpful addition in terms of ther- uations. Examples for disrupting the interferon-alpha apeutic decision making. However, such “idealistic” ap- pathway have been promoted in the treatment of sys- proaches have to be carefully prepared on the basis of temic lupus erythematodes and several strategies have large international collaborative efforts with significant been considered (e.g., Schmidt and and Stew- patient numbers. It is assumed that this ideal goal of any Certain biotechnologicals directed against inter- immune therapy might not be reached within the next feron-alpha are currently undergoing trials in systemic lupus erythematodes. Furthermore, a monoclonal anti- Taken together, the emerging therapeutic targets de- body against and oligonucleotides that inhibit duced from preclinical studies on the immunopathogen- TLR-9 could also be used to reduce interferon- esis (and genetics) of the idiopathic inflammatory myop- alpha/interferon-beta production. Of note, the functional athies, together with the advent of biotechnologicals implications of studies suggesting an important role of opens multiple avenues for future therapeutic options.
this pathway in the pathogenesis of DM, but to some However, the validation of assessment criteria and an extent also in IBM and PM, should be corroborated by international consensus on robust readouts to monitor other groups under preclinical conditions before starting damage from myositis and clinical response profiles from any therapy have to be consolidated before any Cell-based therapies and strategies to modulate the sophisticated immune intervention or therapeutic strat- function of dendritic cells or suppressive T-cell popula- egy can be successfully established for a broad, but het- tion could be considered as well. Those approaches in- erogeneous array of myositis patients. However, large clude vaccination with genetically or cellularly engi- and international collaborative efforts of various clinical neered myeloid dendritic cells designed to induce experts, together with research units, are needed to tolerance, or the development of drugs that promote the bridge the gap between basic research and optimal clin- immunosuppressive properties of immature myeloid- dendritic cells. Furthermore, the recent characterizationof regulatory T-cell populations involved in the patho- Acknowledgment: The work of HW is supported by the
genesis of autoimmunity has been a rewarding area of German Research Foundation and the American Myositis As- basic and clinical research. Regulatory T cells also might sociation. There is no conflict of interests to declare. I amgrateful to Ms. Anke Bauer for editing the manuscript.
be an interesting cellular target for the treatment of in-flammatory myopathies, the corollary being that recon- REFERENCES
stitution of endogenous immune tolerance or promotion 1. Engel AG, Hohlfeld R, Banker BQ. The polymyositis and der- of repair could be achieved by continuous or temporary matomyositis syndromes. In: Engel AG, C Franzini-Armstrong, Neurotherapeutics, Vol. 5, No. 4, 2008 eds. Myology, 2nd ed. New York: Mc Graw Hill, 1994:1335– 26. Choudry V, Cornblath DR, Griffin JW, O’Brien R, Drachman DB.
Mycophenolate mofetil: a safe and promising immunosuppressant 2. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lan- in neuromuscular diseases. Neurology 2001;56:94 –96.
27. Schneider-Gold C, Hartung HP, Gold R. Mycophenolate mofetil 3. Goebels N, Pongratz D. Myositiden. In: Therapie und Verlauf and tacrolimus: new therapeutic options in neuroimmunological neurologischer Erkrankungen, Brandt Th, Dichgans J, Diener HC diseases. Muscle Nerve 2006;34:284 –291.
(Hrsg), 4th ed. Stuttgart: Kohlhammer Verlag, 2003:1284 –1299.
28. Vernino S, Salomao DR, Habermann TM, O’Neill BP. Primary 4. Amato AA, Griggs RC. Treatment of inflammatory myopathies.
CNS lymphoma complicating treatment of myasthenia gravis with Curr Opin Neurol 2003;16:569 –575.
mycophenolate mofetil. Neurology 2005;65:639 – 641.
5. Hengstman GJ, van Engelen BG. Polymyositis: an overdiagnosed 29. Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, Dinsmore ST, McCrosky S. A controlled trial of high-dose 6. Wiendl H, Hohlfeld R, Kieseier BC. Immunobiology of muscle: intravenous immune globulin infusions as treatment for dermato- advances in understanding an immunological microenvironment.
myositis. N Engl J Med 1994;329:1993–2000.
30. Stringer E, Feldman BM. Advances in the treatment of juvenile 7. Dalakas MC. Mechanisms of disease: signaling pathways and im- dermatomyositis. Curr Opin Rheumatol 2006;18:503–506.
munobiology of inflammatory myopathies. Nat Clin Pract Rheu- 31. Cherin P, Pelletier S, Teixeira A, Laforet P, Genereau T, Simon A, Maisonobe T, Eymard B, Herson S. Results and long-term fol- 8. Hohlfeld R, Dornmair K. Revisiting the immunopathogenesis of low-up of intravenous immunoglobulin infusions in chronic, re- the inflammatory myopathies. Neurology 2007;69:1966 –1967.
fractory polymyositis: an open study with thirty-five adult patients.
9. Chevrel G, Goebels N, Hohlfeld R. Myositis: Diagnosis and man- Arthritis Rheumat 2002;46:467– 474.
agement. Pract Neurol 2002;1:4 –11.
32. Dalakas MC. Intravenous immunoglobulin in autoimmune neuro- 10. Hohlfeld R. Polymyositis and Dermatomyositis. In: Karpati G, ed.
muscular diseases. JAMA 2004;291:2367–2375.
Structural and molecular basis of skeletal muscle disease. ISNNeuropath Press 2002, Basel, 221–227.
33. Mastaglia FL, Zilko PJ. Inflammatory myopathies: how to treat the 11. Wiendl H, Hohlfeld R, Kieseier BC. Muscle-derived positive and difficult cases. J Clin Neurosci 2003;10:99 –101.
negative regulators of the immune response. Curr Opin Rheumatol 34. Sekul EA, Chow C, Dalakas MC. Magnetic resonance imaging of the forearm as a diagnostic aid in patients with sporadic inclusion 12. Suber TL, Casciola-Rosen L, Rosen A. Mechanisms of disease: body myositis. Neurology 1997;48:863– 866.
autoantigens as clues to the pathogenesis of myositis. Nat Clin 35. Dalakas MC, Koffman B, Fujii M, et al. A controlled study of intravenous immunoglobulin combined with prednisone in the 13. Needham M, Mastaglia FL. Inclusion body myositis: current treatment of IBM. Neurology 2001;56:323–327.
pathogenetic concepts and diagnostic and therapeutic approaches.
36. Lindberg C, Trysberg E, Tarkowski A, Oldfors A. Anti-T-lympho- cyte globulin treatment in inclusion body myositis: a randomized 14. Dalakas MC. Sporadic inclusion body myositis— diagnosis, patho- pilot study. Neurology 2003;61:260 –262.
genesis and therapeutic strategies. Nat Clin Pract Neurol 2006b;2: 37. Nakayama T, Horiuchi E, Watanabe T, Murayama S, Nakase H. A case of inclusion body myositis with benign monoclonal gam- 15. Askanas V, Engel WK. Inclusion-body myositis, a multifactorial mopathy successfully responding to repeated immunoabsorption.
muscle disease associated with aging: current concepts of patho- J Neurol Neurosurg Psychiatry 2000;68:230 –233.
genesis. Curr Opin Rheumatol 2007;19:550 –559.
38. Rutkove SB, Parker RA, Nardin RA, Connolly CE, Felice KJ, 16. Airio A, Kautiainen H, Hakala M. Prognosis and mortality of Raynor EM. A pilot randomized trial of oxandrolone in inclusion polymyositis and dermatomyositis patients. Clin Rheumatol 2006; body myositis. Neurology 2002;58:1081–1087.
39. Dalakas MC, Rakocevic G, McElroy B, Salajegheh M, Love MH, 17. Marie I, Hachulla E, Hatron PY, Hellot MF, Levesque H, Devulder Shrader J, Levy E, Kirk AD. Alemtuzumab (CAMPATH 1-H) B, Courtois H. Polymyositis and dematomyositis: short term and therapy in sporadic inclusion body myositis (sIBM): a treatment long term outcome, and predictive factors of prognosis. J Rheu- trial in patients with established natural history data. AAN 2007, S57.001. Neurology 2007;12(suppl 168):A361.
18. Choy EH, Isenberg DA. Treatment of dermatomyositis and poly- 40. Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivaku- myositis. Rheumatology (Oxford) 2002;41:7–13.
mar K. Treatment of inclusion-body myositis with IVIG: a double- 19. Miller FW, Rider LG, Chung YL, et al. International Myositis blind, placebo-controlled study. Neurology 1997;48:712–716.
Outcome Assessment Collaborative Study Group. Proposed pre- 41. Walter MC, Lochmüller H, Toepfer M, et al. High-dose immuno- liminary core set measures for disease outcome assessment in adult globulin therapy in sporadic inclusion body myositis: a double- and juvenile idiopathic inflammatory myopathies. Rheumatology blind, placebo-controlled study. J Neurol 2000;247:22–28.
42. Pisoni CN, Cuadrado MJ, Khamashta MA, Hughes GR, D’Cruz 20. Isenberg DA, Allen E, Farewell V, et al. International Myositis and DP. Mycophenolate mofetil treatment in resistant myositis. Rheu- Clinical Studies Group (IMACS). International consensus outcome matology (Oxford) 2007;46:516 –518.
measures for patients with idiopathic inflammatory myopathies.
43. Rowin J, Amato AA, Deisher N, Cursio J, Meriggioli MN. My- Development and initial validation of myositis activity and damage cophenolate mofetil in dermatomyositis: is it safe? Neurology indices in patients with adult onset disease. Rheumatology (Ox- 44. Barohn RJ, Herbelin L, Kissel JT, King W, McVey AL, Saperstein 21. Bunch TW. Prednisone and azathioprine for polymyositis: long- DS, Mendell JR. Pilot trial of etanercept in the treatment of inclu- term follow-up. Arthritis Rheum 1981;24:45– 48.
sion-body myositis. Neurology 2006;66(suppl 1):S123–124.
22. Riley SA, Williams SE, Cooke NJ. Alveolitis after treatment with 45. Wilkes MR, Sereika SM, Fertig N, Lucas MR, Oddis CV. Treat- amiodarone. Br Med J (Clin Res Ed) 1982;284(6310):161–162.
ment of antisynthetase-associated interstitial lung disease with ta- 23. Schnabel A, Hellmich B, Gross WL. Interstitial lung disease in crolimus. Arthritis Rheum 2005;52:2439 –2446.
polymyositis and dermatomyositis. Curr Rheumatol Rep 2005;7: 46. Takada K, Nagasaka K, Miyasaka N. Polymyositis/dermatomyo- sitis and interstitial lung disease: a new therapeutic approach with 24. Fossaluzza V, De Vita S. Clinical differences between ANA/anti- T-cell-specific immunosuppressants. Autoimmunity 2005;38:383– ENA positive or negative primary Sjögren’s syndrome. Clin Rheu- 47. Ochi S, Nanki T, Takada K, Suzuki F, Komano Y, Kubota T, 25. Majithia V, Harisdangkul V. Mycophenolate mofetil (CellCept): Miyasaka N. Favorable outcomes with tacrolimus in two patients an alternative therapy for autoimmune inflammatory myopathy.
with refractory interstitial lung disease associated with polymyo- Rheumatology (Oxford) 2005;44:386 –389.
sitis/dermatomyositis. Clin Exp Rheumatol 2005;23:707–710.
Neurotherapeutics, Vol. 5, No. 4, 2008 48. Greenberg SA. Proposed immunologic models of the inflammatory 61. Bluestone JA, St Clair EW, Turka LA. CTLA4Ig: bridging the myopathies and potential therapeutic implications. Neurology basic immunology with clinical application. Immunity 2006;24: 49. Cooper MA, Willingham DL, Brown DE, et al. Rituximab for the 62. Vugmeyster Y, Kikuchi T, Lowes MA, et al. Efalizumab (anti- treatment of juvenile dermatomyositis: a report of four pediatric CD11a)-induced increase in peripheral blood leukocytes in psori- patients. Arthritis Rheum 2007;56:3107–3111.
asis patients is preferentially mediated by altered trafficking of 50. Chung L, Genovese MC, Fiorentino DF. A pilot trial of rituximab memory CD8ϩ T cells into lesional skin. Clin Immunol 2004;113: in the treatment of patients with dermatomyositis. Arch Dermatol 63. Lowes MA, Chamian F, Abello MV, et al. Increase in TNF-alpha 51. Dinh HV, McCormack C, Hall S, et al. Rituximab for the treatment and inducible nitric oxide synthase-expressing dendritic cells in of the skin manifestations of dermatomyositis: a report of 3 cases.
psoriasis and reduction with efalizumab (anti-CD11a). Proc Natl J Am Acad Dermatol 2007;56:148 –153.
Acad Sci U S A 2005;102:19057–19062.
52. Ferrer E, Moral MA. Spotlight on rituximab as a new therapeutic 64. Leonardi CL. Efalizumab: an overview. J Am Acad Dermatol option for dermatomyositis and thrombotic thrombocytopenic pur- pura. Drug News Perspect 2006;19:482– 484.
65. Greenberg SA, Pinkus JL, Pinkus GS, Burleson T, Sanoudou D, 53. Brulhart L, Waldburger JM, Gabay C. Rituximab in the treatment Tawil R, Barohn RJ, Saperstein DS, Briemberg HR, Ericsson M, of antisynthetase syndrome. Ann Rheum Dis 2006;65:974 –975.
Park P, Amato AA. Interferon-alpha/beta-mediated innate immune 54. Chiappetta N, Steier J, Gruber B. Rituximab in the treatment of mechanisms in dermatomyositis. Ann Neurol 2005;57:664 – 678.
refractory dermatomyositis. J Clin Rheumatol 2005;11:264 –266.
66. Schmidt KN, Ouyang W. Targeting interferon-alpha: a promising 55. Lambotte O, Kotb R, Maigne G, Blanc FX, Goujard C, Delfraissy approach for systemic lupus erythematosus therapy. Lupus 2004; JF. Efficacy of rituximab in refractory polymyositis. J Rheumatol 67. Stewart TA. Neutralizing interferon alpha as a therapeutic ap- 56. Levine TD. Rituximab in the treatment of dermatomyositis: an proach to autoimmune diseases. Cytokine Growth Factor Rev.
open-label pilot study. Arthritis Rheum 2005;52:601– 607.
57. Noss EH, Hausner-Sypek DL, Weinblatt ME. Rituximab as ther- 68. Dzionek A, Sohma Y, Nagafune J, et al. BDCA-2, a novel plas- apy for refractory polymyositis and dermatomyositis. J Rheumatol macytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta 58. Mok CC, Ho LY, To CH. Rituximab for refractory polymyositis: induction. J Exp Med 2001;194:1823–1834.
an open-label pilot study. Ann Rheum Dis 2007;66(suppl II):216.
69. Patole PS, Zecher D, Pawar RD, Gröne HJ, Schlöndorff D, Anders 59. Lebwohl M, Tyring SK, Hamilton TK, et al. Efalizumab Study HJ. G-rich DNA suppresses systemic lupus. J Am Soc Nephrol Group. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003;349:2004 –2013.
70. Zozulya AL, Wiendl H. The role of regulatory T cells in multiple 60. Cooper JC, Morgan G, Harding S, Subramanyam M, Majeau GR, sclerosis. Nat Clin Pract Neurol 2008;4:384 –398.
Moulder K, Alexander DR. Alefacept selectively promotes NK 71. Greenberg SA, Sanoudou D, Haslett JN, Kohane IS, Kunkel LM, cell-mediated deletion of CD45R0ϩ human T cells. Eur J Im- Beggs AH, Amato AA. Molecular profiles of inflammatory myop- athies. Neurology 2002;59(8):1170 –1182.
Neurotherapeutics, Vol. 5, No. 4, 2008



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