Treatment and investigation of idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases which are characterized by symmetrical, proximal muscle weakness, decreased muscle endurance and chronic inflammation in muscle tissue [1–3]. They can be subclassified into dermatomyositis, polymyositis and inclusion body myositis (IBM) according to differences in clinical as well as histopathological features [1, 4]. Dermatomyositis may occur in both adults and children; in this review, we will, however, focus on the treatment of adult forms of myositis only. Myositis may exist as a disease entity on its own or may be linked to another inflammatory connective tissue disease such as systemic sclerosis or mixed connective tissue disease. Myositis may also be associated with a malignancy, this is particularly true for dermatomyositis, but the association with polymyositis is more controversial [1]. The IIM are chronic disorders in most cases and up to two-thirds of patients develop residual functional impairment [5–7]. Several immunosuppressive treatments are available for inflammatory myopathies, yet for many patients recovery is incomplete [5, 8]. Life-long immunosuppressive therapy is often required, adverse side-effects are common and more effective therapies with fewer side-effects are needed [9]. During the last few years, publications of treatments have been dominated by a number of comprehensive review articles, but very few new therapeutic trials have been reported [8, 10–15]. This review will discuss the currently recommended treatment modalities in adult IIM and summarize recently published therapeutic studies mainly focused on cyclosporin A, i.v. immunoglobulin (IVIg) and on non-pharmacological treatment through physical exercise. We also wanted to focus on investigations that could be performed to assess the effect of treatment, and finally to discuss the possibilities of new treatments based on current knowledge of molecular mechanisms believed to be of importance in these disorders [16, 17]. The primary aim for treatment of myositis is to improve muscle function. The molecular background of muscle weakness in myositis is currently largely unknown. There is a lack of correlation between the extent of muscle weakness and degree of muscle inflammation as assessed by the presence of inflammatory cell infiltrates in muscle tissue or serum levels of muscle enzymes [18, 19]. In some cases, there is no detectable infiltrate of inflammatory cells despite muscle weakness and this is particularly common in dermatomyositis and IBM [20, 21]. Furthermore, patients with polymyositis and dermatomyositis often continue to exhibit reduced muscle strength, even after intense immunosuppressive treatment and subsequent disappearance of inflammatory infiltrates [18, 22]. Efforts to date have also been unsuccessful in the identification of other morphological changes, such as muscle atrophy or replacement of muscle tissue by fat, which may be responsible for persistent muscle weakness [22]. Based on these observations, it is likely that factors other than the inflammatory process per se are involved in the mechanisms causing muscle weakness. This hypothesis is further supported by metabolic abnormalities such as reduced levels of phosphocreatine (PCr) and adenosine triphosphate (ATP), as detected by magnetic resonance spectroscopy (MRS), indicating defective energy metabolism in both dermatomyositis and polymyositis cases [23–25]. From the preceding discussion, it is clear that a better understanding of basic pathophysiological mechanisms is needed in order to improve the treatment of these conditions. One way of contributing to such knowledge is obviously to include pathophysiologically directed investigations in longitudinal clinical studies of myositis. Such investigations should include standardized assessments of muscle function, including measurements of muscle strength and endurance, as well as molecular studies on repeated muscle biopsies and repeated MRS investigations. Very few studies have actually assessed the effect of a given therapy on muscle inflammation by investigating the histology of repeated muscle biopsies and correlated these findings to muscle function [18, 26]. Thus, the molecular effect on muscle inflammation of most immunosuppressive drugs used today is largely unknown. Until such studies have been undertaken, we can only adhere to the currently recommended treatments for IIM, which are largely based on uncontrolled studies with assessment of clinical and/or biochemical outcome. Furthermore, these studies are limited by the fact that several different tests of muscle function and strength have been used, which makes comparisons of the outcome between different studies problematic [5, 26–30]. The general recommended treatment of IIM consists of corticosteroids in high doses for the initial few months, with or without other immunosuppressive therapies [1, 8, 11, 15]. Placebo-controlled trials of corticosteroid treatment have never been performed and the optimal initial dosage of corticosteroids, as well as duration of treatment, is therefore uncertain. The only prospective study of corticosteroids found in a literature survey was one in which the effect of prednisone alone was compared to the effect of prednisone together with azathioprine. Eight patients with polymyositis received 60 mg/day of prednisone as a starting dose and six out of eight acquired improved muscle function after 3 yr, although none recovered normal muscle function [31]. In retrospective studies, improved muscle function was observed with an initial dose corresponding to prednisone 40–60 mg/day in 60–80% of the patients assessed by the manual muscle test (MMT) or by one of several muscle function scales [5, 27–29, 32, 33]. It is noteworthy that although a majority of patients improved, a complete recovery rate was reported in only 24–43%. The duration of the high prednisone dose (≥40 mg/day) in these studies varied between 4 days and 9 weeks [5, 20, 28, 33]. In the retrospective study of Henriksson and Sandstedt [5], a significant correlation was determined between the degree of functional improvement using a four-graded score and a mean total dose of at least 0.5 mg/kg/day during the first 3 months compared to 0.3 mg/kg/day. In a more recent retrospective study, a clinical response rate of 86% was recorded after an initial dose of ≥0.75 mg/kg/day [30]. In two other retrospective studies, a spontaneous response rate of 50% was reported [34, 35], while in another small study the spontaneous response rate was 0 [27]. In retrospective studies in which survival rate was used as an outcome measure, no difference was evident between low-dose (<10 mg/day) and high-dose (≥20 mg/day) corticosteroids [36], or between treated and untreated myositis patients [35, 37], even though a higher mortality rate was reported in myositis before the corticosteroid era [38, 39]. These discrepancies in outcome mainly emphasize the limitation of retrospective studies, in which patient groups are not always well defined, and treatment and assessment methods are not standardized. Given the fact that no placebo-controlled trials with the use of corticosteroids have been performed, our interpretation of existing data is that a starting dose of prednisone of 0.75 mg/kg/day (which corresponds to 40–60 mg/day) is likely to suffice in most myositis patients. No data on outcome have been published to support the often recommended dose of 1–2 mg/kg/day (or 80–100 mg/day) for 4–12 weeks [1, 3, 8, 10] as favourable compared to doses of 40–60 mg/day. We would also recommend that the initial high dose of corticosteroids is maintained for 4–12 weeks; this recommendation is based on the observation of a maximal improvement after a mean of 12 weeks [5, 29, 40, 41]. Reduction of the corticosteroid dosage should be guided by improved muscle function [1, 2, 15, 27]. We suggest that tapering of corticosteroid dosages should be initially conducted in small decrements of ∼20% of the daily dosage per month and that tapering could be started when a normal or close to normal muscle function has been achieved, regardless of persisting elevated creatine phosphokinase (CPK) levels. Corticosteroid treatment in consolidation dosages of 5–15 mg/day is often required for several years. A mean duration of treatment of 3 yr was observed in one study, and although some patients still had relapses upon withdrawal of corticosteroids, a gradual tapering of the corticosteroids to withdrawal should be attempted anyway after 2–3 yr [28]. Although most patients with poly- and dermatomyositis respond, at least partially, to corticosteroids, ∼30% of patients do not respond at all [5]. Moreover, in a long-term follow-up study, a substantial number of patients developed increased disability over time due to side-effects of the corticosteroid treatment [9]. These observations emphasize the need for improved treatment for patients with IIM. Several immunosuppressive agents have been reported both as steroid-sparing agents as well as beneficial in patients who are steroid resistant, but few controlled therapeutic trials have been performed. Azathioprine was reported to have a steroid-sparing effect as well as a favourable effect on clinical function compared to prednisone alone in a placebo-controlled trial [31]. Notably, the effect on muscle function was significant not at the 3 month follow-up of the blind study, but after 1 and 3 yr and when the code had been broken, and the steroid-sparing effect was not significant until after 3 yr [18, 31]. The lack of difference in muscle strength, as measured by MMT, after 3 months is not surprising as the patients were given the same corticosteroid dose during this first part of the study and 3 months is far too short a time to expect the full effect of the immunosuppressive treatment [5]. It is more remarkable that there was significantly less functional disability after 12 months treatment as assessed by the relatively crude functional disability index and considering the low number of patients in each group. In another placebo-controlled trial, IVIg was beneficial in treatment-resistant dermatomyositis patients both on muscle function and on muscle histopathology [26]. Adding plasmapheresis had no positive effect compared to corticosteroids alone in a third controlled trial [42]. A combination of oral methotrexate with azathioprine may be of benefit to treatment-resistant poly- and dermatomyositis cases according to a recently published controlled trial [43]. However, the study lacked power to compare the two treatment regimens directly, the other treatment being i.v. methotrexate with leucovorin rescue, which may also benefit some patients with refractory myositis [43]. In addition to these controlled trials, open studies and case reports indicate a positive effect of methotrexate on muscle function in steroid-resistant cases [44, 45]. The doses of methotrexate have varied between 7.5 and 25 mg/week administered orally or i.m., or up to 100 mg/week i.v. [44, 45]. In an additional open retrospective study, male myositis patients with Jo-1 antibodies with incomplete clinical response to corticosteroids were reported to have a more favourable clinical response to additional treatment with methotrexate compared to azathioprine [30]. The effect of cyclophosphamide in IIM is more controversial. In one open study, some patients were reported to benefit from daily oral cyclophosphamide [46], even though i.v. pulse cyclophosphamide was reported to be ineffective in another open study [47]. Chlorambucil had a beneficial effect in a few treatment-resistant dermatomyositis cases [48]. During recent years, cyclosporin A has been relatively widely used in juvenile dermatomyositis [49–52]. In adult myositis, there are only a few reports on the beneficial effects of cyclosporin A, mainly in treatment-resistant poly- and dermatomyositis cases (Table 1) Notably, the effect is often evident a few weeks of In one open study of adult dermatomyositis, cyclosporin A was reported to be beneficial as a without corticosteroids on cyclosporin A in the treatment of adult myositis during the last yr on cyclosporin A in the treatment of adult myositis during the last yr in addition to the controlled trial of IVIg in polymyositis and dermatomyositis, a few open studies have been In one such study, IVIg as an initial treatment without corticosteroids was to disease in patients with polymyositis and dermatomyositis In another open study, IVIg was beneficial on muscle strength, function and muscle levels in a few treatment-resistant cases with dermatomyositis or but not in patients with IBM From the studies on IVIg treatment in poly- and dermatomyositis one can that treatment-resistant cases with dermatomyositis could benefit from IVIg but further studies are needed to the effect in patients with However, IVIg not patients with dermatomyositis as a time of is required [26]. of IBM a This entity was first as treatment-resistant polymyositis and was by other case reports on myositis patients being refractory to corticosteroid treatment and with a corresponding histopathology a few therapeutic trials including IBM patients have been reported on in the In retrospective studies, of IBM patients to corticosteroids with or improved muscle function, but none recovered some improved on but none had a complete response In a prospective trial, patients improved muscle function after combination therapy with methotrexate and and had a of disease In the same study, i.v. methotrexate with leucovorin in improved muscle function in cases and of disease in In a recently published placebo-controlled study, improvement of muscle function was observed in patients after a 3 month trial with but there was no significant difference compared to the There were effects on muscle groups of the and however, were of clinical the patients to the IVIg therapy according to own it had a difference in daily and of In muscle strength was found to be in all patients given IVIg in an open trial From these limited of therapeutic trials performed in it is still controversial immunosuppressive drugs have a beneficial effect in this disease some patients have a or effect on clinical but far there are no reports on recovery of muscle function. This therapeutic also the fact that the the clinical is even less well for this of myositis than for poly- and dermatomyositis, and there is still a the inflammatory in muscle tissue are primary or in persisting inflammation in muscle tissue was observed after a of 60 months of corticosteroid treatment in one study the in another study, a decreased cell was observed in muscle tissue after an of months of corticosteroid treatment, but still muscle function These studies emphasize the need for more controlled trials including patient as well as the need for investigations on the effects of a given therapy both on muscle function and on the and molecular in muscle interpretation of these therapeutic reports in IIM is that immunosuppressive drugs should be from the of as was by some the for this being both the high of side-effects and the of to corticosteroid treatment to the data azathioprine should be the first as a Although methotrexate is often used in clinical the of this in IIM still to be in a controlled The data are less clear the beneficial effect of cyclosporin A, IVIg or compared to corticosteroids and more controlled trials are before general therapeutic can be the functional in patients with myositis, the non-pharmacological have received but controversial treatment of IIM is physical exercise. of of causing disease patients with myositis have been recommended to exercise. studies, however, have that could be performed in patients with poly- and dermatomyositis without increased muscle inflammation assessed by or by muscle biopsies and magnetic resonance and with beneficial effect on muscle function. effect on muscle strength after and for weeks was reported in patients with poly- and dermatomyositis in a recently published controlled study of patients There is one on in IBM including patients who increased muscle strength after 12 weeks of without increased disease as assessed by levels The effects of in addition to treatment in patients with disease have only been in a limited number of patients although with beneficial effect on muscle strength and function, and without of increased disease physical should be during the of treatment to the of chronic muscle weakness is still and can only be by a controlled The recommendation today is to include physical when disease to this could include a to or a on a or in the for the who is to treatment for patients and for the of the effects of therapies in controlled trials, there is a need to disease and to disease from that used of serum such as and never been as follow-up and are by [20, (Table The most often used assessments for therapeutic are clinical of muscle strength and serum muscle [5, 29, muscle and have been as for both and for assessment of disease Although there is a general that muscle function is the most for therapeutic there is no as to this should be Moreover, as a of muscle function could be the of both muscle inflammation and chronic changes, the of muscle function to be with one or several that could muscle Thus, there is a need for a standardized outcome which disease such an index is currently being developed for juvenile dermatomyositis and it will be to develop a for adults with myositis. for the of idiopathic inflammatory myopathies for the of idiopathic inflammatory myopathies weakness is a of decreased strength and endurance which should be when a to muscle function. patients with myositis both muscle strength and muscle however, some particularly who have recovered muscle function during treatment, can often a strength test or but do repeated tests or a using the same muscle group. A test which muscle endurance is more and is more likely to muscle function than a strength test in this of patients. Furthermore, the muscle tests should which are to the patients. The most used for muscle function is the with the There are several to this its to is low and has not been in follow-up of improvement has never been upon or it patient and is time A more to muscle strength is the but its use is limited by the high A better was observed with the use of a another to muscle however, its in a longitudinal study has not been these tests strength and not the of these tests to the patients has not been is a to muscle strength as well as endurance, but is not available in a and a to the A the time needed to from a was reported with to changes, but the limitation is its to the The of Myositis endurance and strength, and is to use in a follow-up study of It a to the but not However, for this we also determined a limitation in to in cases with a low degree of muscle weakness. tests based on have been used, but not patients with IIM, have functional disability and there is a lack of upon a of improvement in these scales [5, Thus, the of Myositis is by our the most and functional test for clinical but it still further it is to be used as a test in therapeutic muscle function alone not between and chronic a combination with investigations is rate and other are only elevated in a limited number of cases with IIM, and are not in assessment of disease There is also a limitation to the use of muscle enzymes such as as the only of disease in some myositis patients with disease the of was normal 29, and other patients have persistent elevated muscle without other of disease and normal muscle function reports also that serum could be in the normal even when and biochemical were observed and in therapeutic trials including and levels were more common than improved muscle function [30]. levels are also by muscle enzymes such as and are less of muscle than as both and are in other such as the Thus, in many cases with IIM, serum muscle enzymes may not be a of disease and there is a need for additional measurements to assess disease histology is the most way to assess muscle changes, but it may not be an way to the of therapy with the current most the open muscle due both to the for the patients and the This could be by muscle biopsies which a and which can be performed with for the and which for repeated biopsies This can be performed by the in an with a very low and could be as a for assessment of disease in clinical trials The with could be reduced by several biopsies from the same way to this is to use to an for muscle to be knowledge of disease and the effect of treatment at a molecular could be by repeated muscle biopsies and by findings to clinical outcome. can be used to in muscle and to assess disease but it muscle for It may be more and than for of IIM, in cases in which muscle enzymes are normal The and of in the of myositis are on the in muscle of polymyositis and dermatomyositis was observed using and/or short recovery normal were found using In chronic polymyositis and dermatomyositis atrophy of and the were reported using a combination of and and the elevated replacement correlated with the duration of the disease is needed to between and as to in both and and may be by of is also a assessment to use for follow-up studies as a correlation was determined between increased and and muscle function and disease published data from therapeutic studies support the of with and of which to normal when there was clinical improvement after therapy Thus, it is that could into of the myositis. is however, to the between and clinical such as muscle strength, muscle function, muscle histopathology and the of serum A number of groups have used MRS to inflammatory muscle disease These studies have focused on which assessment of muscle such as and In dermatomyositis cases with and levels were while the of to was increased to even at These metabolic abnormalities were further with In dermatomyositis, and levels and the were to but during the was elevated with no significant these studies support the hypothesis that metabolic are at least involved in the of the muscle weakness and the need for therapies to the currently used other and even after of inflammation MRS may have the to be used as a to therapeutic regimens studies have reported the use of MRS to assess patients with myositis. In a of a juvenile dermatomyositis MRS determined an low at the of the disease and the high compared to at 3 months of treatment This observation may during of the which after treatment by and in muscle during chronic of the disease In another study, other muscle such as and were significantly different in chronic polymyositis and dermatomyositis cases compared to These abnormalities were evident in patients with normal as well as elevated studies are needed to spectroscopy is an for disease metabolic were also recorded in the of IIM patients. of the muscle such as and were all significantly higher than in levels of creatine were in this disease using methods for many but the of other has not been levels in were also reported in other general muscle and levels were reduced with treatment in polymyositis and dermatomyositis and levels to be to clinical outcome MRS metabolic may have the to be a for assessment of disease in IIM patients and to the of therapy in an MRS in with new for the biochemical of in myositis patients. The observed using and spectroscopy were determined to be more than the as and biochemical were often observed in patients with normal MRS together with may have the to the biochemical and that are significant in disease In may an for disease and response to therapy Several muscle groups were used for both and follow-up in a few studies of IIM This however, to be a for follow-up studies as there was no correlation between and muscle strength in the only longitudinal study performed to date Furthermore, not to be for of which muscle to for for In the IIM are a of muscle disorders with a substantial number of patients who develop a chronic disability and a reduced of due to persisting decreased muscle function as well as to side-effects of corticosteroid Until more controlled trials have been performed, we mainly have to upon of uncontrolled trials for treatment for patients with IIM. These studies support initial treatment with prednisone in starting doses of 0.75 mg/kg/day for weeks with tapering doses according to muscle function of the high corticosteroid doses that are required, an additional immunosuppressive would be optimal and controlled trials are of follow-up studies clinical outcome with molecular findings in repeated muscle biopsies and an increased knowledge the as well as the effect of treatment at a molecular will be increased knowledge of which and are in the inflammatory process will it to develop more therapies for myositis to the of new treatment modalities which are currently being in A of the IIM is the metabolic as a of the persisting muscle weakness. The use of MRS to assess metabolic a new of disease assessment that to be further in follow-up of treatment that should be in the of the IIM is physical which was recently not only to be but also to improve muscle strength in myositis patients the of improved a disease would be very could develop such a disease index for adult myositis, by the which has started for juvenile dermatomyositis for