Truetime 56000 Manual Muscle
IntroductionDermatomyositis and polymyositis are systemic inflammatory disorders characterized by symmetric proximal muscle weakness and commonly involve other organ systems, such as the skin (in dermatomyositis) and lung. Treatment decisions are typically empirically based due to few controlled trials and a lack of targeted immunosuppression. Expert consensus supports high-dose oral prednisone as first-line therapy; however, as many as 30%–40% of patients may fail to respond, and up to 40% or more experience major adverse events with long-term steroid use. Steroid-sparing or alternative immunosuppressive therapies, including methotrexate, azathioprine, cyclosporine, and mycophenolate mofetil, have a long onset of action and risks, including toxicity to the kidneys, liver, and bone marrow.
Intravenous immunoglobulin is considered a second-line therapy for dermatomyositis, but not for polymyositis. Materials and methodsAll patients in this retrospective case series review were female, aged 25–68 years, with diagnoses confirmed on muscle biopsy (see ). ACTH gel was approved and paid for by each patient’s health insurance. All patients received 80 U (1 mL) of ACTH gel via subcutaneous injection.
Four patients received ACTH gel twice weekly for 12 weeks and one patient received ACTH gel once weekly. Patient 1A 45-year-old woman diagnosed with dermatomyositis presented with a diffuse erythematous rash across her chest and finger extensors, clear periungual telangiectasias, and mechanic’s hands, with progressive arm and leg muscle weakness. She had an elevated creatine phosphokinase of 4500, and muscle biopsy showed perifascicular atrophy and inflammation. Autoantibody testing showed no myositis-specific autoantibodies.The patient’s treatment history since 2004 included intravenous immunoglobulin, azathioprine, rituximab, cyclosporine, and methotrexate. The patient initially responded well to treatment with prednisone ≤40 mg/day (the patient would not agree to take 40 mg/day of prednisone due to side effects of weight gain, mood changes, and severe gastric symptoms), intravenous immunoglobulin 2 g/kg per month (she experienced moderate side effects to intravenous immunoglobulin, including headache, chills, and nausea), and azathioprine 150 mg/day. In 2007, she experienced a disease exacerbation, and rituximab 375 mg/m 2 for two doses and then a single dose every 3 months for 12 months was added to ongoing prednisone, azathioprine, and intravenous immunoglobulin. The patient showed good improvement in her rash and muscle strength.
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Her disease became more active in 2009, including muscle weakness, severe rash, and significant nail bed changes, and she had an inadequate response to treatment with prednisone, intravenous immunoglobulin, cyclosporine 200 mg/day, and methotrexate 15 mg/week.The patient received treatment with ACTH gel concomitantly with prednisone 20 mg/day and intravenous immunoglobulin 2 g/kg per month. Her creatine phosphokinase levels prior to starting ACTH gel therapy were normal. By 8 weeks, her skin rash had improved markedly.
Proximal leg strength increased from 3/5 to 4+/5 in her iliopsoas and quadriceps. She was able to get out of a chair and walk independently. The patient tolerated the treatment well without any significant side effects. HbA 1c remained normal. Since completing ACTH gel treatment, she has been managed adequately with intravenous immunoglobulin 2 g/kg per month, prednisone 20 mg/day, and methotrexate 15 mg/week. Patient 2A 25-year-old woman diagnosed with juvenile dermatomyositis presented at the age of 11 years with muscle weakness, classic skin changes, and calcinosis. She had an elevated creatine phosphokinase of 56,000 and a muscle biopsy showing perifascicular atrophy and inflammation.
Autoantibody testing showed no myositis-specific autoantibodies. At the time of transition to adult care in 2004, she was very weak and required the use of a walker.Her treatment history as a pediatric patient included prednisone up to 100 mg/day, resulting in significant cushingoid side effects, mycophenolate mofetil 3000 mg/day, which resulted in palpitations, azathioprine 200 mg/day, intravenous immunoglobulin 2 g/kg per month, cyclosporine 200 mg/day, and methotrexate 20 mg/week. Since transitioning to adult care, she had received rituximab, cyclosporine, intravenous immunoglobulin, azathioprine, and pulse methylprednisolone. The patient showed a good response to rituximab (375 mg/m 2 for two doses and then a single dose every 3 months for 12 months), and was maintained on intravenous immunoglobulin, cyclosporine, and azathioprine until a disease exacerbation in 2007. The patient did not show improvement on rechallenge with rituximab over the next 6 months; her strength worsened, and she again required a walker for ambulation. She did not show improvement in response to pulse methylprednisolone 1 g/week for 8 weeks.The patient received ACTH gel concomitant with ongoing intravenous immunoglobulin 2 g/kg per month, azathioprine 200 mg/day, and cyclosporine 200 mg/day.
Her creatine phosphokinase and aldolase levels prior to initiation of ACTH gel were in the low-normal range, reflecting significant previous muscle atrophy. The patient noted improved strength and independent ambulation within 8 weeks of treatment.
Her muscle enzymes decreased from 800 to 100. The patient’s iliopsoas strength improved from 3/5 to 4/5 and her quadriceps strength increased from 3−/5 to 4+/5. She also reported improvement in her rash and nail bed changes. Within 6 months of completing ACTH gel, and while on intravenous immunoglobulin and azathioprine, weakness in her proximal leg muscles again declined to 3+/5. She was started on tacrolimus for 6 months with no benefit.
The patient was restarted on ACTH gel, 80 U once a week with partial improvement in strength. Treatment with ACTH gel was increased to 80 U twice weekly, and the patient has shown a good response. Her leg muscle strength improved to 4+/5. She has continued on ACTH gel for 7 months, in combination with intravenous immunoglobulin and azathioprine. Her strength is 5/5 in all muscle groups except her iliopsoas, where it is 4/5. The patient has been able to return to work and is ambulating independently.
The patient tolerated ACTH gel treatment well without any significant side effects. Her HbA 1c and fasting glucose levels have remained normal, and there has been no change in her bone density as measured by densitometry. Patient 3A 43-year-old woman diagnosed with dermatomyositis presented with diffuse erythematous rash, profound diffuse muscle weakness, and joint pains. The patient had an elevated creatine phosphokinase of 2500, and muscle biopsy showed perifascicular atrophy and inflammation. Autoantibody testing showed no myositis-specific autoantibodies.Treatment history since 2009 included prednisone up to 60 mg/day, weekly pulse methylprednisolone 1 g/day, and intravenous immunoglobulin as high as 2 g/kg per month. Rituximab was denied by the patient’s insurance company.
The patient became pregnant in 2010, and during pregnancy and subsequent childbirth, she experienced a marked decrease in muscle strength and difficulty walking. Lower extremity strength responded well to pulse methylprednisolone 1 g/day for 5 days, prednisone 60 mg/day, and monthly intravenous immunoglobulin 50 g increased to 2 g/kg. However, upper extremity muscle weakness continued, and she was not able to hold her baby. The patient disliked high-dose prednisone due to side effects of significant weight gain and elevated glucose.
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She also experienced severe side effects to high-dose intravenous immunoglobulin, including rash, headache, fevers, and malaise.Treatment with ACTH gel was initiated concomitant with prednisone 30 mg/day and intravenous immunoglobulin 2 g/kg per month. Her creatine phosphokinase levels prior to starting therapy were mildly elevated at 647. The patient’s diffuse strength increased after 12 weeks and was accompanied by a drop in her creatine phosphokinase to 154. She was able to hold her baby and she became independent with her activities of daily living.
Most notably, deltoid strength increased from 2/5 to 4/5 and triceps strength from 3/5 to 4/5. Her myalgias also improved markedly.
The patient tolerated the treatment well without any significant side effects or change in HbA 1c. Since completing ACTH gel, she has been managed adequately with prednisone 35 mg/day and intravenous immunoglobulin 50 g per month. Patient 4A 55-year-old woman diagnosed with polymyositis presented with marked limitation of her extraocular muscles bilaterally and mild proximal muscle weakness in her arms. She had a mildly elevated creatine phosphokinase of 650, and a muscle biopsy of the right deltoid showed inflammatory changes consistent with polymyositis. An orbital magnetic resonance imaging scan showed inflammation of the extraocular muscles. Testing for acetylcholine receptor antibodies and antithyroid antibodies, an electromyogram with repetitive nerve stimulation and single-fiber testing, and thyroid profile were all normal.
Genetic testing for oculopharyngeal muscular dystrophy was normal. Autoantibody testing showed a positive rheumatoid factor, a positive antinuclear antibody 1:1260, and no myositis-specific autoantibodies.Treatment history since 2007 included prednisone, mycophenolate mofetil, and intravenous immunoglobulin. The patient was initially treated with prednisone 60 mg/day. Her eye movements and double vision responded very well, and prednisone was tapered to 20 mg/day. The patient experienced a disease exacerbation in 2009 with increased arm and leg weakness that prevented her from engaging in activities with her grandchildren. Prednisone was increased to 60 mg/day and resulted in improved muscle strength; however, the patient strongly disliked prednisone due to mood-related side effects. Mycophenolate mofetil 1500 mg twice daily was added to treatment and prednisone was tapered and withdrawn.
The patient’s strength and eye movements again worsened, and intravenous immunoglobulin 2 g/kg per month for 6 months showed no benefit.The patient began treatment with ACTH gel concomitant with ongoing mycophenolate mofetil 1500 mg twice daily. She had normal creatine phosphokinase and aldolase levels prior to starting therapy with ACTH gel. Proximal muscle strength increased after 12 weeks; most notably, the patient’s deltoids and triceps improved from 3/5 to 4+/5. No improvement occurred in her extraocular muscles, but the patient reported that she was again able to participate in activities with her grandchildren. The patient tolerated the treatment well, without any significant side effects or increase in HbA 1c.
Since completing ACTH gel, she has been managed adequately with intravenous immunoglobulin 2 g/kg per month and mycophenolate mofetil 1500 mg twice daily. Patient 5A 68-year-old woman diagnosed with polymyositis presented with muscle weakness, difficulty getting out of a chair and climbing stairs, and weak grip strength that was reduced to 40 lb. Myositis-specific autoantibody tests were normal. Muscle biopsy of the quadriceps was negative for inclusion body myositis and was consistent with polymyositis.The patient’s treatment history since 2003 included pulse methylprednisolone, pulse cyclophosphamide, intravenous immunoglobulin, mycophenolate mofetil, and rituximab. The patient responded well to initial combination treatment with pulse methylprednisolone 1 g/week for 8 weeks and pulse cyclophosphamide 1 g/m 2 per month for 6 months. Treatment with pulse methylprednisolone was stopped due to recurrent infections, including hospitalization for severe pneumonia, and intravenous immunoglobulin 2 g/kg per month was started.
The patient responded well to combination treatment with monthly pulse cyclophosphamide and intravenous immunoglobulin. The patient was weaned off intravenous immunoglobulin, and mycophenolate mofetil 1500 mg twice daily was added. In 2008, the patient experienced a disease exacerbation, and rituximab 375 mg/m 2 for two doses and then a single dose every 3 months for 12 months was added to ongoing mycophenolate mofetil. In 2011, the patient again experienced disease exacerbation that improved with pulse methylprednisolone and mycophenolate mofetil. Medicare then refused payment for continued pulse methylprednisolone, and the patient had 3 months without steroid therapy. During this time, her energy and strength worsened and she returned to occasional use of a walker.The patient began treatment with ACTH gel 80 U once weekly, concomitant with ongoing mycophenolate mofetil 1500 mg twice daily. Her creatine phosphokinase levels prior to starting therapy with ACTH gel were mildly elevated at 632.
After 12 weeks of treatment with ACTH gel, her creatine phosphokinase decreased to 388. She tolerated the treatment well, without an increase in HbA 1c or any weight gain, sleep disturbance, or gastrointestinal symptoms, which had been significant side effects while on pulse methylprednisolone. The patient noted significant improvement in her strength and no longer required the use of a walker. Her muscle strength improved from 4/5 to 5/5 in her quadriceps and to 4+/5 in her iliopsoas. The patient will continue ACTH gel treatment as long as insurance coverage continues. DiscussionThis retrospective case review of the responses of five patients to ACTH gel in the short-term treatment of worsening dermatomyositis or polymyositis found clinically significant improvement in all patients. Effective and tolerable treatment options for patients with refractory dermatomyositis and polymyositis are limited.
ACTH gel may provide a novel anti-inflammatory and immunomodulatory option, given its possible mechanisms of action beyond steroidogenesis.Although ACTH gel is approved for use in dermatomyositis and polymyositis, it is not well known as a potential treatment option because of a paucity of clinical data. In these five patients seen in our clinic over the past four years, the decision to use ACTH gel was motivated by increasing weakness in all patients (one patient also had worsening rash), increasing diplopia in one patient, and inadequate response to previous immunosuppressive therapies in all patients. Improvement on manual muscle testing and patient-reported function in daily activities was seen in all patients, and patients uniformly reported that these changes had a significant impact on their quality of life and their level of independent function. Manual muscle testing scores have been associated with functional abilities, such as walking and completion of activities of daily living in patients with polymyositis or dermatomyositis, as well as in patients with other neuromuscular diseases.– In functional terms, mean manual muscle testing strength grade.