Targeted Treatment of the Idiopathic Inflammatory Myopathies

A 52-year-old woman presented with a 2-week history of progressive joint and muscle pain with stiffness in the upper arm and leg musculature. She had been exercising regularly for years and was in good physical shape. She also described a temperature of 38.2 ° C, Raynaud’s phenomenon, symptoms of carpal tunnel syndrome, fatigue, palpitations, and shortness of breath. She was not taking any medications. On physical examination, no reduction of muscle strength was noted as measured by manual muscle test (MMT; explained later), but muscle endurance as measured by the functional index 2 (FI-2; explained later, see also Table 14-1 and reference 1) was reduced by 30% to 55% symmetrically in both the upper and lower extremity musculature and in the neck flexors. She was admitted to the hospital. On laboratory investigation, the thyroid stimulating hormone (TSH) level was moderately increased to 31 mE/L (0, 4–4, 7), T4 was normal at 12 pmol/L (range 8–12 pmol/L), and T3 was reduced slightly at 3, 0 pmol/L (3, 5–5, 4). Serum creatine phophokinase (CK) levels were increased to 1932 IU/L. Electrophysiologic investigation revealed spontaneous activity in the biceps brachia, the deltoid, and the vastus lateralis muscles bilaterally. There were small light red skin eruptions overlying the knuckles and elbows. Chest x-ray examination and computed tomography (CT) examinations of the lungs revealed objective signs of interstitial lung disease (ILD) bilaterally, and enlargement of the heart including both the right and left chambers. There was no sign of pericarditis. Echocardiography revealed a small volume of pericardial fluid (3- to 5-mm layer). There were no signs of pulmonary hypertension, and there was no significant reduction of left ventricular function. Pulmonary function tests including vital capacity (VC) and total lung capacity (TLC) were reduced to less than 80% of the predicted values. Likewise, the single breath transfer factor for carbon monoxide (TLCO) was reduced to 50% of the predicted value. Electrocardiography (ECG) showed sinus tachycardia without any arrhythmia. There were no laboratory signs of infection. Antinuclear antibodies (ANAs) were absent; anti-Jo-1 antibodies were present by immunoblot analysis. A muscle biopsy was performed by the percutaneous conchotome method from the right vastus lateralis muscle. Four small pieces of muscle tissue were obtained. The biopsy revealed scattered atrophic muscle fibers and signs of muscle fiber degeneration. Type II fiber atrophy was not present. Major histocompatibility complex-1 ( MHC-1) was upregulated in a small number of predominately perifascicular fibers ( Fig. 14-1 ). Some scattered CD 68 positive cells were also seen (macrophage marker). A diagnosis of Jo-1–positive dermatomyositis (DM) with heart and lung involvement was made. On further evaluation, including mammography, gynecologic examination, and CT of the abdomen, no sign of malignancy was found. The patient was started on small doses of levothyroxine replacement 4 days after admission. TSH normalized after 4 weeks of treatment with levothyroxine replacement. She was also given methylprednisolone 500 mg IV on 3 consecutive days and then oral prednisolone 50 mg (0.75 mg/kg). Concomitantly she received cyclophosphamide (CyX) pulses, 1000 mg monthly for 6 months. Tapering of prednisolone was started 6 weeks after diagnosis, initially in small decrements of 15% of the daily dosage per month. Six weeks after starting treatment (3 months after the onset of symptoms), muscle weakness had improved according to the FI-2, but the patient still had weakness of the neck flexors. Serum CK had steadily decreased and was now within the normal range (120 µ/L). At 3 months, there was a further gradual improvement, and muscle function was almost normal as measured by the FI-2. Shortness of breath resolved completely after 4 months. Lung function tests were almost normalized, and a CT thorax showed almost complete regression of interstitial findings at 6 months. At the same time, echocardiography revealed regression of the previously noted cardiac enlargement. Muscle strength was completely normal at 6 months, serum CK had normalized, and a repeat muscle biopsy from the contralateral vastus lateralis muscle showed no inflammatory cell infiltrates and no MHC-1-positive fibers

Table 14-1

The Functional Index 2

Tasks	Position	Pace (beats/min)	Maximal Number of Repetitions	Short Instruction
1. Shoulder flexion *	Sit on chair without back support	40	60	Raise the arm forward/upward
2. Shoulder abduction	Sit on chair without back support	40	60	Raise the arm to the side/upward
3. Head lift	Lay on a bench with horizontal head support without a pillow	40	60	Lift the head as much as possible
4. Hip flexion	Lay on back on a bench with straight legs	40	60	Lift one leg at the time (heel 40 cm from the bench)
5. Step test	Climb a 25 cm high stool	40	60	When climbing use the right leg, descending with the left.
6. Heel lift	Stand on both feet with balance support	80	120	Lift the heels as much as possible
7. Toe lifts	Stand on both feet with your hips and back against a wall	80	120	Lift the toes as much as possible

Each task can be performed bilaterally or on the dominant side. Each task is scored as the number of correct performed repetitions giving a profile of muscle endurance impairment of the upper and lower extremities as well as the neck muscles. More detailed information, including pictures of all tasks, is included in an appendix in the original publication.

* Use a 1 kg weight cuff around the wrist.

After 6 months, the patient was on prednisolone 17.5 mg daily and continued tapering by 10% every 3 to 4 weeks. Additionally, she received methotrexate SC starting with 7.5 mg weekly, which was increased to 15 mg/week after 1 month. A carpal tunnel release was performed after 10 months, with resolution of the symptoms. One year after diagnosis, the patient was taking prednisolone 7.5 mg and MTX 15 mg weekly SC, as well as calcium and vitamin D supplementation and alendronic acid 70 mg weekly. She was going on daily walks with her dog for 1 hour and gradually increased to 2 hours. Already during the third week after diagnosis she had started doing home exercises in a myositis-specific training program, which entailed training five times weekly with increasing loads under supervision of a physical therapist ( Fig. 14-2 ), and 1 year later she was still performing these exercises regularly.

The differential diagnosis in this case was hypothyroidism versus DM. The patient had a discrete skin rash and she had symptoms such as fatigue that are common in both diagnoses. We considered the possibility that the patient’s hypothyroidism might have caused the muscular symptoms. However, her hypothyroidism was of a mild degree, with T3 and T4 levels being almost normal, and clinical symptoms such as muscle weakness are uncommon in this situation. Patients with hypothyroidism may have changes on muscle biopsy such as type II fiber atrophy, which, however, was not present in this case. On the other hand, MMT did not reveal any muscle weakness, which made a diagnosis of myositis less probable. The FI-2 and muscle biopsy findings, and to a lesser extent the presence of anti-Jo-1 antibodies, elevation of CK level, Gottron’s papules, and electrophysiologic changes contributed to a definitive diagnosis of DM in this case. This case illustrates the difficulty in diagnosing inflammatory myopathies if muscle weakness is minor. Pulse CyX therapy in combination with steroids may be an appropriate therapy alternative in some cases of severe polymyositis (PM)/DM. In this case, we chose CyX as second-line therapy because of lung and heart involvement. An important aspect of this case was the short delay between onsets of symptoms and initiation of treatment, which may have contributed to the complete resolution of symptoms. Another instructive aspect of this case is the fact that muscle function as measured by MMT was normal at disease onset, whereas FI-2 showed reduced muscle endurance.

CASE 1

INTRODUCTION

The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases that are characterized by symmetric, proximal muscle weakness; decreased muscle endurance; and chronic inflammation in muscle tissue. They can be subclassified into DM, PM, and inclusion body myositis (IBM) according to differences in clinical as well as histopathologic features. DM may occur in both adults and children; in this chapter, however, we 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 DM, whereas the association with PM is more controversial. The IIMs are a somewhat heterogenous group of disorders, which is also reflected in their different responses to immunosuppressive therapies. Many studies have used Bohan and Peter criteria and the Griggs criteria for IBM to subgroup the patients. Although these are the most frequently used diagnostic criteria, they have some limitations because even the subgroups PM or DM are not always homogeneous, with differences in response to treatment. Thus, there is a need for revised classification criteria to augment future studies of disease mechanisms.

Most patients with PM or DM present with subacute or slowly progressive proximal muscle weakness that is usually symmetric and represents a major source of disability for these patients. They often experience difficulty raising the head when supine, lifting, carrying, climbing steps, dressing, and even walking on flat ground. Many patients need to use the handrail on stairways as a means of pulling themselves up. The patients also typically experience low muscle endurance, and their muscles are easily fatigued. As an example, they may be able to walk up one set of stairs, but then they cannot lift their legs any more and have to rest. The flexor muscles of the neck are affected more than the extensors. The musculature of the trunk can also be affected, which leads to difficulty in arising from supine positions. In contrast, the facial musculature is generally spared. Muscle pain is less common than muscle weakness and fatigue. Typically, the main discomfort arises after a workload and is often expressed by the patients as a sensation of “lactic acid in their legs.”

IBM causes weakness and atrophy of distal and proximal muscles; involvement of quadriceps muscles and deep finger flexors are often clues to the diagnosis. Patients often present with falls because their knees collapse due to quadriceps muscle weakness, or they have difficulty performing certain tasks such as turning keys owing to weakness of finger flexors. Neck flexors and extensors are frequently affected. Dysphagia occurs in up to 60% of patients with IBM, leading to choking episodes. Facial muscle weakness is not common, and extraocular muscles are not affected. Sensory function is usually normal. The tendon reflexes, although preserved early in the disease, can diminish in the late stages as atrophy of major muscle groups becomes evident. Disease progression is slow but steady and resembles that of a muscular dystrophy. Most patients with IBM require an assistive device, such as a walker or wheelchair, within several years of onset. IBM patients rarely have muscle pain.

The IIM are chronic disorders in most cases and up to two thirds of patients develop sustained functional impairment. Several immunosuppressive treatments are available for the inflammatory myopathies, yet for many patients, recovery is incomplete. Life-long immunosuppressive therapy is often required, adverse side effects are common, and more effective therapies with fewer side effects are needed.

EXTRAMUSCULAR MANIFESTATIONS

Extramuscular manifestations are common features in IIM. The most common extramuscular manifestations are from skin, affecting all with DM and some with PM. In both PM and in DM the lungs, joints, gastrointestinal (GI) channel, and heart may be affected, indicating that IIMs are systemic inflammatory diseases. They also frequently co-occur with other defined rheumatologic diseases such as systemic sclerosis, Sjögren’s syndrome, and mixed connective tissue disease and less often with systemic lupus erythematosus (SLE) or rheumatoid arthritis. IBM is usually evident as an isolated muscle disease, although there are reports of an association with Sjögren’s syndrome.

PULMONARY DISEASE

Pulmonary complications constitute important clinical manifestations of DM or PM. The lungs may be involved either primarily with inflammation in the lung tissue, ILD, or as a complication of muscle weakness. Pulmonary involvement as a complication of PM or DM was primarily described by Hepper et al, aspiration pneumonia, ventilatory insufficiency and interstitial pneumonia being the three most important types of associated lung involvement. Interstitial pneumonia or ILD can be a serious complication of PM or DM. The reported prevalence of pulmonary involvement in PM or DM varies between 5% and 46% in cross-sectional studies, depending on whether clinical, radiologic, functional, or pathologic criteria have been used. According to a recent reported prospective study, ILD is a common (65%) early manifestation in patients with PM or DM and is not always related to clinical symptoms. The presence of ILD in patients with myositis affects the prognosis, with increased morbidity and mortality, and this often also has an influence on the choice of immunosuppressive treatment.

CUTANEOUS MANIFESTATIONS

Dermatologic manifestations usually precede the onset of muscle disease, and patients may experience significant cutaneous symptoms; however, studies of DM severity have historically focused with greater attention on the muscle disease. The characteristic and possibly pathognomonic cutaneous features of DM are the heliotrope rash and Gottron’s papules ( Fig. 14-3 ). The heliotrope rash is composed of a violaceous erythematous rash with or without edema in a symmetric distribution involving the periorbital skin. Sometimes this sign is subtle and may involve only a mild discoloration along the eyelid margin. At other times, massive edema may develop. A heliotrope rash is rarely observed in patients with lupus erythematosus or scleroderma. Gottron’s papules are present over bony prominences, particularly the metacarpophalangeal joints, the proximal interphalangeal joints, and the distal interphalangeal joints. They may also be found overlying the elbows, knees, and feet. These lesions consist of slightly elevated, violaceous papules and plaques. There may be a slight scale on some occasions. Within the lesions, there is often telangiectasia. These lesions may be clinically confused with lesions of SLE.

Skin calcinosis is a disabling complication, most commonly evident in children or young adults. Hard yellow nodules can arise over bony prominences. The deposits of calcium may erupt onto the skin surface and be the sites of secondary infection.

HEART INVOLVEMENT

Clinically manifest heart problems are relatively infrequent in patients with PM or DM. Subclinical cardiac involvement is more common and the frequency varies depending on the methods used. ECG changes are most common, and ECG abnormalities were observed in 32.5% to 72% of patients. ECG abnormalities observed in PM and DM patients include atrial and ventricular arrhythmias, bundle branch block, AV blocks, high-grade heart block, prolongation of PR intervals, ventricular premature beats, left atrial abnormality, abnormal Q waves, as well as nonspecific ST-T wave changes. In the absence of controlled studies, it is still uncertain whether these manifestations are more frequent in the IIM than in an age- and gender-matched population.

GASTROINTESTINAL INVOLVEMENT

The most common GI symptom is dysphagia, caused by the weakness of the pharynx or esophagus and disordered esophageal motility. Esophageal dysfunction occurs in 15% to 50% of patients.

OTHER EXTRAMUSCULAR MANIFESTATIONS

Constitutional symptoms, such as fatigue and fever, often precede or accompany flares of disease and usually respond to glucocorticoids. Weight loss may relate to impaired swallowing. Raynaud’s phenomenon is common and can often be managed by calcium channel blockers. Joint symptoms, which are nonerosive and involve both small and large joints, can improve by treatment with glucocorticoids.

TREATMENT

Pharmacologic Treatment

The treatment of the IIM is still largely empirical. Idiopathic inflammatory myopathies are rare diseases, and there are few randomized prospective clinical studies that have compared different methods of treatment ( Table 14-2 ). Many studies of pharmacologic intervention have included a patient mix of acute and chronic disease. Spontaneous recovery from IIM has rarely been reported. Patients with DM or PM respond to treatment differently than patients with IBM or myositis associated with another connective tissue disease. Assessment of therapeutic interventions is also limited owing to a lack of standardized methods for assessing IIM; this not only limits the ability of clinicians to evaluate therapeutic responses in individual patients, but also hinders interpretation of the few trials that have been conducted. During the past 30 years, there have been 24 prospective studies of treatments of adult myositis. Few of these were blinded and/or controlled trials (see Table 14-2 ). In addition to confirming the diagnosis and assessing extramuscular manifestations, defining disease activity by assessing changes in muscle strength is critical for managing the patient with IIM.

Table 14-2

Prospective Treatment Studies in Adult Patients with Polymyositis, Dermatomyositis, and Inclusion Body Myositis

Study	Design	Diagnosis	Number of Patients	Treatment	Effect of Therapy	Muscle Biopsy	Muscle Function Method
Bunch et al 1980	Prospective, randomized, Double blind	PM/DM	16	Azathioprine/prednisolone versus placebo/prednisolone	Moderate, No difference between groups	Before/after	MMT
Bunch 1981	Follow up after 3-year, uncontrolled	PM/DM	16	Azathioprine/prednisolone versus placebo/prednisolone	Study group require less pred	No	MMT
Cronin et al 1989	Prospective open label	PM/DM/IBM	11	Monthly IV cyclophosphamide	No effect	No	MMT
Cherin et al 1991	Prospective open label	PM/DM	20	Monthly IVIG	Good effect	No	MMT
Miller et al 1992	Prospective, double-blind	PM/DM	42	Plasma exchange versus leukopheresis versus sham apheresis	No effect	No	MMT
Dalakas et al 1993	Prospective, double-blind Placebo controlled, cross over	DM	15	Monthly IVIG	Good effect Prior study group	Before/after	MMT
Barohn et al 1995	Prospective open label	IBM	8	Prednisolone	No effect	Yes	MMT
Leff et al 1993	Prospective open label, cross over	IBM	11	Oral methotrexate/azathioprine versus biweekly methotrexate IV	No effect	No	MMT
Cherin et al 1995	Prospective, open label	PM/DM	57	Plasma exchange	No effect	No	MMT
Villalba et al 1998	Prospective, randomized open label, cross over	PM/DM	30	Oral methotrexate/ azathioprine versus biweekly intravenous methotrexate	Combination treatment prior	No	MMT
Adams et al 1999	Prospective, open label	PM/DM	16	Intravenous fludarabine	Moderate effect in subgroup	No	MMT
Oddis et al 1999	Prospective, open label	IIM		Oral tacrolimus		No	MMT
Muscle study group 2001	Prospective, randomized controlled	IBM	30	β INF	No effect No difference between groups	No	MMT, MVICT
Venkovsky et al 2000	Prospective, randomized controlled	PM/DM	36	Cyclosporine A versus methotrexate	Methotrexate prior cyclosporine	No	MEFT
Danieli et al 2002	Prospective, open label	PM/DM	20	Cyclosporine A/ prednisolone versus cyclosporine A/ prednisolone/ IVIG/ plasma exchange	Cyclosporine A/prednisolone/IVIG/ prior plasma exchange no effect	No	MMT
Levine et al 2005	Prospective open label pilot	DM	6	Rituximab	Good	Yes baseline	MMT
Badrising et al 2002	Prospective randomized double-blind placebo-controlled	IBM	44	Methotrexate	No effect	No	MMT
Lindberg et al 2003	Prospective, open label randomized	IBM	11	ATG versus methotrexate	ATG group prior	Before/after	MMT
Barohn et al, 2006	Prospective open label pilot	IBM	9	Eternacept	No effect	No	MMT
Chung et al 2007	Prospective open label	DM	8	Rituximab	Moderate	No	MMT
Mok et al 2007	Prospective open label	PM	4	Rituximab	Moderate	No	MMT
Barbasso et al 2007	Prospective open label	PM/DM, IBM	13	Monthly IVIG	No effect on myopathy	Before/after	FI
Hengstman et al 2008	Prospective open label	PM/DM	6	Infliximab	No effect	No	MMT
Dastmalchi et al 2008	Prospective open label pilot	PM/DM, IBM	13	Infliximab	No effect	Before/after	FI, MMT

ATG, anti-T-lymphocyte globulin; β INF, beta-interferon; DM, dermatomyositis; FI, functional index; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathies; IVIG, intravenous immune globulin; MEFT, muscle endurance functional testing; MMT, manual muscle testing; MVICT, maximum voluntary isometric contraction testing; PM, polymyositis.

The primary aim for treatment of myositis is to improve muscle function. There are only a few treatment studies in which investigations of repeated muscle biopsies has been included as an outcome measure. Thus, the molecular effect on muscle inflammation of most immunosuppressive drugs used today is largely unknown.

Investigations for Assessment of Treatment

Clinicians need to measure disease activity and to differentiate disease activity from chronic, irreversible changes that cause disability. The currently used diagnostic tools, muscle biopsy, elevation of serum enzyme activity, such as CK, and electrophysiologic investigation, have various limitations. The most frequently used assessments for therapeutic responses are clinical evaluation of muscle strength and serum muscle enzyme activity. Recently, magnetic resonance imaging (MRI) has been investigated as a possible tool for both diagnostic purposes and for assessment of disease activity. Importantly, reduction of muscle function can be the result of both active muscle inflammation and of chronic changes, and therefore, any measurement of muscle function must be combined with assessments that reflect active muscle inflammation.

The MMT has been used in trials to assess isometric muscle strength in myositis. However, in patients with mild impairment, the MMT had limited reliability. Another limitation of this measurement (and related ones) is that they measure strength, whereas patients with PM and DM often report impaired muscle endurance rather than, or in addition to, muscle weakness. The FI in myositis was the first functional impairment outcome measure developed specifically for patients with PM and DM. The FI is based on repetitive movements involving selected muscle groups to capture decreased muscle endurance; it was validated as reliable regarding its ability to discriminate patients from healthy individuals. The FI is useful in assessing patients with moderate to severe impairment but it has some ceiling and floor effects. A revised version, the FI-2, which also measures muscle endurance, has no ceiling or floor effects, and possesses satisfactory construct validity and interrater and intrarater reliability. It is not time consuming to administer, is well tolerated by patients with all stages of disease, and does not require any expensive equipment or formal training (see Table 14-1 ). We recommend this measure for use in routine clinical care and clinical research. The disease-specific questionnaire Myositis Activities Profile (MAP) was developed in Sweden to assess limitations in activities of daily living and is valid for patients with PM and DM. However, a possible limitation of a predefined questionnaire is that all questions might not be relevant for all patients. Therefore the MacMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), which was originally developed for arthritis patients, was validated for patients with PM and DM. The MACTAR focuses on activities that are limited and important to improve for each individual and also contains questions about other aspects of health. The short form 36 (SF-36) is a generic questionnaire assessing quality of life that has been proven useful for myositis patients.

Muscle Biopsy

Muscle biopsy is the gold standard for diagnosis of the IIM. Obtaining a muscle specimen for histopathologic study is an important component of the diagnostic evaluation for most suspected myopathies. Histopathologic evaluation of muscle biopsies is also important to exclude other myopathies and to identify subsets of IIM. A muscle biopsy technique that allows for repeated biopsies is important to assess the effect of treatment at the tissue level. One such muscle biopsy technique is the percutaneous conchotome biopsy or the semiopen muscle biopsy. This method has become widely used in Sweden and other Scandinavian countries, including our rheumatology clinic, during the past 20 years for both diagnostic and research purposes, but has received little attention outside Scandinavia. The percutaneous conchotome muscle biopsy technique gives a good size sample that allows for diagnostic evaluation and has a high yield in patients with myositis. It is a simple procedure and is easy to learn and to perform, with a low complication rate and minimum discomfort for the patient. The method can preferably be used as a diagnostic tool and repeated biopsies can help assess the effect of a given therapy for both clinical and research purposes. The percutaneous conchotome muscle biopsy technique is a sensitive method to simply and safely make diagnostic evaluations and to assess the effect of a given therapy on muscle tissue in patients with idiopathic inflammatory myopathies. This semiopen biopsy technique can easily be performed by the rheumatologist in an outpatient clinic with a very low complication rate, and could be included as a tool for assessment of disease activity in clinical trials. The problem with ‘skip lesions’ could be reduced by taking several biopsies from the same incision. Another way to overcome this problem is to use MRI to select an appropriate site for muscle to be biopsied. Further knowledge of disease pathogenesis and the effect of treatment at the molecular level could be obtained by performing repeated muscle biopsies and by correlating histologic findings with clinical outcome.

Various methods for sampling muscle tissue are available, and each has advantages and disadvantages. An open biopsy generally harvests the largest amount of tissue and can be performed on numerous muscles, but this technique is invasive and gives a large scar. Conversely, needle biopsy has become or is becoming the standard method of muscle biopsy at some institutions in North America, Europe, and elsewhere in the world. Needle biopsy can be performed rapidly and is less invasive and less expensive, but the disadvantage is the smaller amounts of tissue per sample.

Glucocorticoids

The generally recommended treatment for DM and PM consists of glucocorticoids in high doses for the initial few months, with or without other immunosuppressive therapies. Placebo-controlled trials of glucocorticoid treatment have never been performed, and therefore, the optimal initial dosage of glucocorticoids, as well as duration of treatment, is uncertain. In retrospective studies, improved muscle function was observed with an initial dose corresponding to prednisone 40 to 60 mg/day in 60% to 80% of the patients assessed by the MMT or by one of several muscle function scales. It is notable that although a majority of patients improved, a complete recovery rate was reported in only 24% to 43%.

Lundberg and associates examined muscle biopsies obtained from 10 patients with PM or DM before and after 12 to 24 weeks of treatment with prednisolone, 0.75 mg/kg/day. Strength improved in seven patients. Important changes were observed in the follow-up muscle biopsies, including a significant decrease in the expression of MHC-1 antigens on muscle cells. The major issue with the use of glucocorticoids to treat IIM is, of course, the development of significant side effects. Indeed, in studies of long-term outcomes of patients with IIM, steroid-induced side effects are major causes of disability. In IBM, the results of several uncontrolled trials of glucocorticoids have shown stabilization or temporary improvement in muscle strength in some patients; however, these improvements are not usually maintained. In a prospective trial of high-dose prednisolone for up to 12 months in eight patients with IBM muscle strength continued to deteriorate despite a fall in the serum CK concentrations, and repeat muscle biopsies showed an increase in the numbers of vacuolated and amyloid-containing fibers, despite a reduction in the numbers of T cells. Thus, the bulk of the evidence does not support the use of glucocorticoids in most patients with IBM.

Immunosuppressive Agents

Although most patients with PM or DM respond, at least partially, to glucocorticoids, about 30% of patients do not respond at all. Moreover, in a long-term follow-up study, a substantial number of patients developed increased disability with time owing to the side effects of glucocorticoid treatment.

Several immunosuppressive agents have been reported both as steroid-sparing agents as well as being beneficial in patients who are steroid resistant, but few controlled therapeutic trials have been performed. Azathioprin (AZA) was reported to have a steroid-sparing effect as well as a favorable effect on clinical function compared with prednisone alone in a placebo-controlled trial. However, treatment with AZA for 3 months did not have any impact on inflammation in the muscle as assessed by muscle biopsy (see Table 14-2 ).

Retrospective studies, open prospective studies, and case reports have indicated a positive effect of MTX on muscle function in steroid-resistant patients with DM/PM, but there have been no prospective controlled studies of this agent. The doses of MTX varied between 7.5 and 25 mg/week administered orally or IM, or up to 100 mg/week IV. In an additional open retrospective study, male patients with myositis with Jo-1 antibodies with incomplete clinical response to glucocorticoids were reported to have a more favorable clinical response to additional treatment with MTX compared with AZA. In a randomized double-blind placebo-controlled study, 44 patients with IBM were treated with MTX. Quantitative muscle strength testing scores declined in both treatment groups but less so while on active treatment. This difference was not significant. There were no differences in MMT total scores, activity scale scores, and patients’ own assessments after treatment. CK decreased significantly in the MTX group. The conclusion was that oral MTX did not slow the progression of muscle weakness. In a prospective, randomized study, the combination of oral MTX with AZA was compared with high-dose intravenous MTX with leucovorin rescue. Both groups of patients with treatment-resistant PM/DM experienced modest improvements, but without a significant difference between the two treatments.

The efficacy of CyX in IIM is unclear. In one openlabel study, some patients were reported to benefit from daily oral CyX, whereas IV pulse CyX was reported to be ineffective in another open study.

There are a few reports of beneficial effects of cyclosporin A (CyA), mainly in treatment-resistant adult PM and DM cases. In one open-label study of adult DM, CyA was reported to be beneficial as a first-line drug without corticosteroids. Another controlled trial was conducted by Vencovsky and colleagues. They investigated effectiveness and tolerance of treatment with CyA or MTX added to glucocorticoids in patients with severe, active PM and DM. Administration of MTX or CyA added to glucocorticoids was associated with clinical and laboratory improvement. Changes in CK and interleukin-1 receptor anatagonist (IL-1Ra) levels were not associated with parameters of clinical disease severity measured in this study. No patient recovered completely.

Intravenously administered high dosages of immunoglobulins (IVIG) are used in various autoimmune diseases, including the IIM. In a placebo-controlled trial, high-dose IVIG was beneficial in treatment-resistant DM patients, both regarding muscle function and muscle histopathology. The therapeutic mechanisms of IVIG in DM are not known. Although the clinical effects were accompanied by decreased intercellular adhesion molecule 1 (ICAM-1) and MHC class I expression in repeat muscle biopsies, the number of patients that were subject to a repeat biopsy was small. The effect of IVIG in PM patients was less certain. High doses of IVIG are usually well tolerated, but a drawback of high-dose IVIG treatment is the high cost. We performed an open, prospective trial in 13 treatment-resistant patients (six with PM, four with DM, two with IBM, and one adult person with juvenile-onset DM) who had signs of persistently active inflammatory disease. The patients were treated with IVIG 2 g/kg 3 times at monthly intervals. Clinical evaluations as well as FI, CK levels, and muscle biopsies were performed before treatment and after the third IVIG infusion in all subjects. Additional biopsies were taken 24 to 48 hours after the first infusion for molecular studies. Improved muscle function as measured by FI was recorded in three patients (one with PM, one with DM, and one with IBM), and CK levels decreased by more than 50% in five out of nine individuals with elevated levels, but median CK levels were not changed. Skin rash improved in three of four patients with DM. T cells, macrophages, MHC class I antigen on muscle fibers, IL-1, ICAM-1, and vascular cell adhesion molecule 1 (VCAM-1) expression and membranolytic attack complex (MAC)-deposits on capillaries were present to an equal degree in biopsies before and after IVIG treatment ( Fig. 14-4 ). The relative frequency of muscle fiber type I and type II fibers was unchanged. High-grade muscle inflammation persisted after treatment in all patients. No correlation was seen between the clinical response and changes in proinflammatory molecules or fiber type characteristics. We concluded that the effects of IVIG treatment in IIM are limited.