Hospital Medicine

Inflammatory myopathies

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Inflammatory myopathies

I. What every physician needs to know.

Inflammatory myopathies are characterized by immune-mediated muscle injury. The three most common inflammatory myopathies are dermatomyositis, polymyositis, and inclusion body myositis.

Both dermatomyositis and polymyositis present with symmetric proximal muscle weakness developing over weeks to months. While dermatomyositis can be seen in both children and adults, polymyositis is rarely seen in childhood. Both disorders occur through autoimmune-mediated destruction of muscle, however their mechanisms differ slightly. In dermatomyositis, complement-mediated inflammation of capillary endothelial cells results in muscle ischemia and infarction. Conversely, polymyositis immunopathogenesis involves direct T cell mediated muscle cytotoxicity. Once felt to be a subset of polymyositis, inclusion body myositis is now recognized as a separate clinical entity with a more insidious onset and pathology characterized by both autoimmune and degenerative mechanisms.

The overall incidence of the inflammatory myopathies is approximately 2 in 100,000. Each of these diagnoses differ in their clinical presentation, pathologic mechanism and response to therapy.

II. Diagnostic Confirmation: Are you sure your patient has an inflammatory myopathy?

When the possibility of inflammatory myopathy is raised by history and physical exam, the diagnosis is confirmed by serum creatinine kinase (CK), electromyography (EMG) and muscle biopsy. The original diagnostic criteria were proposed by Bohan and Peter in the 1970s with two further classification criteria proposed in the past ten years.


The characteristic heliotrope rash greatly raises the likelihood of dermatomyositis and is required to make the diagnosis of "definite" dermatomyositis. If the skin manifestations are absent but other clinical characteristics and muscle biopsy are consistent with dermatomyositis, then the diagnosis is "probable" dermatomyositis.

Throughout the disease course, CK can range from normal to as greatly elevated as fifty times the normal value. EMG typically reveals a myopathic pattern, with increased spontaneous activity including complex repetitive discharges and fibrillations as well as motor unit potentials with short duration and low amplitude during voluntary activation. Because these features are not unique to dermatomyositis, or any myopathy in particular, the primary purpose of the EMG is to distinguish myopathic etiologies of muscle weakness from neurologic causes.

Definitive diagnosis of dermatomyositis can be made with muscle biopsy. Under light microscopy, dermatomyositis-affected muscles display perivascular and interfascicular inflammatory infiltrates without involvement within the fascicles. As a result of what is felt to be a microvascular ischemic process, biopsy displays evidence of groups of fascicles that are affected surrounding vessels as opposed to uniform distribution of inflammation, necrosis, and atrophy throughout the muscle. This perifascicular atrophy is pathognomonic for dermatomyositis. Another characteristic finding is intramuscular vasculature with endothelial hyperplasia, microthrombi and capillary obliteration.

The term amyotrophic dermatomyositis refers to patients who present solely with the classic skin findings associated with dermatomyositis but with no muscle weakness or biopsy findings for more than 6 months. Most patients with amyotrophic dermatomyositis will develop muscle weakness and typical dermatomyositis muscle biopsy findings within 5 years.


Polymyositis is more of a diagnosis of exclusion. "Definite" polymyositis is diagnosed in a patient with development of proximal muscle weakness over weeks to months with other potential causes of myopathy ruled out and muscle biopsy consistent with polymyositis. The characteristic skin findings of dermatomyositis and evidence of toxic or infectious myopathy are absent.

CK is elevated and may be up to fifty times the normal value. As in dermatomyositis, EMG also displays a myopathic pattern. However, muscle biopsy reveals a predominantly intrafascicular pattern of inflammation with a preponderance of cytotoxic (CD8+) T cells bound to major histocompatibility complex class I (MHC-I) antigen within muscle fibers. Affected fibers are scattered throughout muscle parenchyma as opposed to dermatomyositis' perivascular distribution. The CD8/MHC-I complex is also seen in inclusion body myositis, however the vacuoles/degenerative changes seen in inclusion body myositis are absent in polymyositis.

The diagnosis of "probable" polymyositis is made when clinical characteristics are consistent with polymyositis and other etiologies of myopathy have been ruled out but typical histopathology is absent on muscle biopsy.

Inclusion body myositis

Inclusion body myositis is suspected in patients with proximal and distal muscle weakness developing over years.

CK may be normal but also can be elevated as high as ten times normal. EMG generally reveals a myopathic pattern but can occasionally show high amplitude, long duration motor unit potentials that could be interpreted as neurogenic.

Muscle biopsy is diagnostic of "definite" inclusion body myositis in approximately 85% of cases revealing characteristic congo red staining deposits and rimmed vacuoles. The CD8/MHC-I endomysial inflammation that is seen in polymyositis is also present in inclusion body myositis.

If the clinical presentation suggests inclusion body myositis but muscle biopsy fails to show red rimmed vacuoles and congo red staining deposits, then the diagnosis is deemed "probable" inclusion body myositis, "clinical" inclusion body myositis or "PM/IBM". In these cases a repeat biopsy from a different site is often helpful.

A. History Part I: Pattern Recognition:

Dermatomyositis and polymyositis

Dermatomyositis can occur at any age and presents as symmetric proximal weakness developing over weeks to months along with typical skin findings. More acute presentations can occur in dermatomyositis but rarely. Because the primary muscles affected are the hip flexors and deltoids, patients typically present with inability to rise from a seated position, climb stairs, comb their hair or brush their teeth. Distal muscle involvement, usually presenting with inability to perform fine motor tasks, is rarely impaired but may occur late in the course of dermatomyositis. Facial muscles are spared but neck and pharyngeal muscles are typically involved. Muscle pain and tenderness to palpation may occur in up to 50% of patients but is generally mild.

Several distinct rashes occur in dermatomyositis distinguishing it from polymyositis or inclusion body myositis. The cutaneous manifestations tend to occur prior to muscle weakness but can develop at the same time. Erythematous eruptions can occur on the knuckles, upper eyelids, shoulders and neck in a V distribution.

Patients with polymyositis present with very similar complaints as patients with dermatomyositis but do not develop any of the aforementioned rashes.

Inclusion body myositis

Inclusion body myositis typically presents very differently than dermatomyositis and polymyositis. The onset is insidious, with an average time to diagnosis from symptom onset of about 5 years. Patients are generally more than 50 years old at the time of presentation, though symptoms may start in their 30s. Compared to polymyositis and dermatomyositis, muscle weakness is more commonly asymmetric and there is typically earlier involvement of distal muscles. The most common complaint at presentation is weakness in the quadriceps muscles, including difficulty with rising from squatting, climbing ladders, and walking up or down stairs. Another common complaint at presentation is difficulty with hand grip and fine motor skills as a result of distal muscle involvement.

Facial muscles may be mildly involved but pharyngeal and neck muscles often have more severe involvement than dermatomyositis and polymyositis. This leads to dysphagia and issues with inability to keep one's head upright which can become a significant issue from a nutrition standpoint.

Extramuscular manifestations

Inflammatory myopathies can affect other organ systems in nearly half of cases.

Pulmonary complications can either be the result of thoracic muscle weakness or interstitial lung disease (ILD). ILD prevalence is approximately 40% for all inflammatory myopathies, though estimates vary widely. Patients with positive anti-Jo antibody, which is found in about 20% of patients, is associated with ILD in almost 90% of cases. Patients with amyotrophic dermatomyositis are also more likely to develop ILD.

Cardiac involvement can result in arrhythmias, especially tachyarrhythmias and atrioventricular (AV) conduction delays, cardiomyopathy, and heart failure. Patients with dermatomyositis and polymyositis also appear to be at increased risk for myocardial infarction.

Esophageal involvement is also common, which can lead to dysphagia and aspiration, further compounding pulmonary issues.

Patients with dermatomyositis can have subcutaneous calcifications that can lead to ulceration, infection, and joint contractures.

Systemic symptoms can also be present, especially if there is concomitant connective tissue disease.

B. History Part 2: Prevalence:

The annual incidence of dermatomyositis and polymyositis is estimated at 2 per 100,000, with a prevalence ranging from 5 to 22 per 100,000. Both dermatomyositis and polymyositis are seen twice as often in women. The peak incidence occurs between 40 to 50 years of age, though dermatomyositis, in particular, is known to affect persons of all ages, including children. Inclusion body myositis is much less common, with an estimated prevalence of 70 per million. It is generally seen in patients above 50 years old, and is three times more common in men than women.

There have been multiple studies examining rates of malignancy in inflammatory myopathies with some conflicting results. However, data overall suggest an increased risk of malignancy in patients with dermatomyositis.

Concomitant autoimmune disorders can occur in all inflammatory myopathies including systemic sclerosis (especially in dermatomyositis), lupus, rheumatoid arthritis, mixed connective tissue disease and Sjögren's syndrome.

C. History Part 3: Competing diagnoses that can mimic disease inflammatory myopathies

Drug-induced myopathies. The patient's medication list should be reviewed for potential inciting medications such as statins, corticosteroids, hydroxychloroquine, interferon alpha, penicillamine, beta-blockers, certain antibiotics, cimetidine, zidovudine, cyclosporine, and amiodarone. Other toxins such as cocaine and alcohol can also cause a myopathy or rhabdomyolysis.

Necrotizing myopathy. Although phenotypically similar to polymyositis, autoimmune necrotizing myopathy differs in its histological appearance on muscle biopsy, which shows necrotic muscle fibers without abundant inflammatory cells. It is most commonly seen after exposure to statins, but unlike a drug-induced myopathy, it does not resolve with withdrawal of the drug.

Hypothyroidism and Cushing's. These patients may present similarly and should have appropriate endocrine work-up as part of an initial evaluation.

Muscular dystrophy. This can often be easily differentiated from dermatomyositis and polymyositis because of its slow development over years, but this can make it difficult to distinguish from inclusion body myositis. Muscle biopsy, trial of steroids, and genetic testing can help with more difficult cases.

Neuromuscular junction pathology including myasthenia gravis and Lambert-Eaton syndrome. Myasthenia gravis tends to have more prominent ocular and facial muscle involvement which may not be present in Lambert-Eaton. These diagnoses can be made with nerve conduction studies and single fiber EMG.

Metabolic disorders affecting carbohydrate and lipid metabolism. A common cause is carnitine deficiency. Patients present with rhabdomyolysis, myoglobinuria, and severe myalgias.

Infectious myopathy. This can be caused by a host of different pathogens including parasites, viruses such as human immunodeficiency virus (HIV), and bacteria (most commonly Staphylococcus aureus, yersinia, and Streptococccus) with presentations ranging from subtle weakness to acute pyomyositis.

Amyotrophic lateral sclerosis (ALS). Examination reveals upper motor neuron signs, CK is typically normal and EMG shows evidence of denervation.

Cutaneous manifestations of dermatomyositis may appear similar to seborrheic dermatitis, systemic lupus erythematosus (SLE), psoriasis, contact dermatitis or lichen planus.

D. Physical Examination Findings.

Muscle examination reveals proximal symmetric weakness in both dermatomyositis and polymyositis patients. Inclusion body myositis patients are more likely to have asymmetric weakness. They more commonly have weakness of quadriceps and more distal muscles, including poor hand grip.

Cutaneous findings in dermatomyositis:

  • Heliotrope rash: upper eyelids display violaceous discoloration often accompanied by periorbital edema.

  • Shawl sign: erythematous scaling patches in V distribution across anterior neck and covering shoulders.

  • Gottron's papules: considered to be a hallmark of dermatomyositis. Extensor surfaces of metacarpal and interphalangeal joints display discrete erythematous papules and plaques (can also involve knees and elbows).

  • Subcutaneous calcifications: can lead to joint contractures, vascular insufficiency, ulceration, and infections.

  • Malar rash: does not spare nasolabial folds (helps distinguish it from SLE).

  • Periungual capillary loop changes: skin surrounding nail beds may be erythematous with evidence of dilated and tortuous blood vessels. More subtle changes may need the use of a dermatoscope or otoscope to appreciate. Severity often mirrors overall disease activity. Present in dermatomyositis and polymyositis but also can be seen in systemic sclerosis, lupus and mixed connective tissue disease.

  • Mechanic's hands: hyperkeratotic lesions along palms and digits with resulting cracks and fissures. When present, this usually occurs as part of the antisynthetase syndrome.

E. What diagnostic tests should be performed?

When inflammatory myopathy is suspected, muscle enzymes, EMG and muscle biopsy can usually establish a diagnosis. Skin biopsy findings are non-specific in dermatomyositis, but may rule out other autoimmune conditions.

Dermatomyositis is associated with an increased risk of malignancy. Initial evaluation should include a thorough history and physical examination, including a pelvic examination, chest x-ray, blood count and chemistry, urinalysis (UA), and age-appropriate cancer screening. Further potential evaluation should be guided by these initial results. The most common associated malignancies are ovarian, gastric, colon, breast, melanoma, and non-Hodgkin's lymphoma.


CK is part of the initial laboratory evaluation of potential inflammatory myopathy. Although it often parallels disease activity, CK may be normal in both dermatomyositis and inclusion body myositis. CK may be as elevated as ten times normal in inclusion body myositis and up to fifty times elevated in dermatomyositis and polymyositis. CK should be drawn prior to EMG, which may elevate CK as a result of muscle trauma. Transaminases and lactate dehydrogenase (LDH) may also be elevated, which may be incorrectly interpreted as liver disease.

Autoantibody testing should also be undertaken. The classic myositis-specific antibodies include:

  • Anti-Jo1 is positive in roughly 20% of patients with inflammatory myopathy and has a strong association with ILD. This association is termed antisynthetase syndrome when myopathy and ILD are associated with Raynaud's, mechanic's hands and arthropathy.

  • Anti-signal recognition particle (anti-SRP) antibody is specific for polymyositis and is associated with aggressive and difficult-to-control disease.

  • Anti-Mi-2 is a classic marker for dermatomyositis and is associated with good response to corticosteroids and an overall favorable prognosis.

Newer autoantibodies specific for myositis include:

  • Anti-MDA5/CADM140 is associated with amyotrophic dermatomyositis.

  • Anti- TIF1γ/α is associated with malignancy in dermatomyositis.

The following are not specific for myopathies but should be considered in the initial workup:

  • Antinuclear antibody (ANA) is positive in up to 80% of patients with dermatomyositis and polymyositis.

  • Anti-Ku and anti-Scl antibodies are often positive in overlap syndromes, in which patients have myositis and coexisting connective tissue disease (most often scleroderma when these two antibodies are present).


The selected biopsy site can be determined by clinical examination, potentially with the assistance of EMG and magnetic resonance imaging (MRI) findings. Ultimately, a muscle biopsy is the definitive test for diagnosis. Classic pathologic findings are discussed above under "diagnostic confirmation". Chest x-ray should be performed on initial evaluation to assess for ILD and, in the case of dermatomyositis, malignancy.


Whole-body computed tomography (CT) scans to screen patients with dermatomyositis to evaluate for malignancy are not necessary. Further imaging to evaluate for malignancy should be based on an initial history and a physical examination (including a pelvic exam), complete blood count (CBC) and chemistry, urinalysis, chest X-ray and age-appropriate cancer screening.

III. Default Management.

Specific targets for immunomodulation have yet to be clearly identified in inflammatory myopathies. The current approach to therapy includes initiation of general immunosuppression with corticosteroids followed by transition to steroid-sparing agents when possible. Intravenous immunoglobulin (IVIG) has also been shown to be effective in both dermatomyositis and polymyositis.

A. Immediate management.

Corticosteroids are considered the mainstay of treatment. Expert consensus recommends initiation of prednisone at 1 mg/kg daily as early in the disease course as possible. Pulsed, high-dose intravenous (IV) steroids can be considered if disease is severe on presentation or if dysphagia or risk of aspiration is a major concern. Prednisone at a dose of 1 mg/kg per day is typically continued for 4-6 weeks, followed by a slow taper over a 6-12 month period, with a goal of finding the lowest effective dose required for disease control.

Most patients with dermatomyositis and polymyositis will have at least some response to corticosteroids; however, there is often a need to add (or transition to) non-steroidal immunosuppressive medications in the case of steroid failure or intolerable adverse effects of steroid therapy. In the case of steroid failure, however, the possibility of an alternative diagnosis, such as inclusion body myositis, should be considered. Repeat EMG or muscle biopsy may be warranted.

Inclusion body myositis currently is a steadily progressive disease, and there is minimal evidence to support the use of glucocorticoids or other immunosuppressive agents. Still, expert consensus recommends a trial of prednisone, 1 mg/kg per day, and consideration of azathioprine or methotrexate. These agents should be discontinued if there is a continued decline in strength.

B. Physical Examination Tips to Guide Management.

An assessment of potential extramuscular manifestations and disease severity on admission, including respiratory failure, dysphagia or aspiration risk, and cardiac involvement, can assist with triage and determination of other diagnostic and therapeutic needs while hospitalized. These features tend to confer a poorer prognosis.

Re-evaluation of muscle strength as well as assessment of ability to perform activities of daily living helps determine treatment efficacy and potential dose change of steroids or addition of non-steroidal immunosuppressive medications. A follow-up examination for evaluation of extramuscular manifestations, including rash, respiratory status, dysphagia, and cardiac involvement, can also help assess overall disease activity.


Treatment efficacy should not be guided by serial CK levels. Rather than the CK level, clinical improvement of strength exam as well as subjective improvement should be taken into account.

D. Long-term management.

Most patients with polymyositis and dermatomyositis will require additional immunosuppressive medications besides steroids.

Methotrexate and azathioprine are considered first-line steroid-sparing agents. They may be started at the time of initial treatment, either concurrent with steroids or as an alternative in the setting of contraindication to steroids. Alternatively, they may be added when attempts to taper steroids to acceptable long-term doses fail.

Patients are typically considered to have resistant disease if they have no improvement after 3 months on steroids with or without the above steroid-sparing agents. The best evidence-based therapeutic options for resistant disease are rituximab and IVIG. IVIG appears to be more effective in dermatomyositis, with minimal evidence of benefit in polymyositis. Furthermore, its long-term use has not been explored due to cost concerns. Alternative agents include mycophenalate, cyclosporine, cyclophosphamide, tacrolimus, and combined methotrexate and azathioprine.

Other treatment modalities are geared towards specific symptoms and include physical therapy and occupational therapy to maintain muscle strength and ability to perform activities of daily living. Occasionally, dilation and botulin toxin injections are used for esophageal manifestations.

For patients with inclusion body myositis, IVIG may be considered only in the case of advance dysphagia, where it has shown some benefit. There is no evidence to recommend treatment with any of the other agents typically used in resistant dermatomyositis and polymyositis. Because of the lack of pharmacologic options, physical, occupational, and speech therapy should be especially emphasized.

E. Common Pitfalls and Side-Effects of Management

Ensure correct diagnosis if initial treatment fails. In some cases a repeat biopsy may be necessary. This most frequently occurs with initial diagnoses of polymyositis which are later diagnosed as inclusion body myositis or limb girdle muscular dystrophy.

Methotrexate: initial oral dosing 15 mg (PO) weekly and uptitrate as needed. Effect is typically seen in approximately 2 months. Side effects include neurotoxicity, pulmonary fibrosis, hepatotoxicity, and bone marrow (BM) toxicity, which can be mitigated by concurrent administration of folic acid.

Azathioprine: 1.5-2 mg/kg. Effect seen in approximately 4-6 months. Side effects include BM toxicity and hepatotoxicity.

Mycophenalate: up to 3 g per day. Effect is seen in 2-3 months. Generally well tolerated but side effects include opportunistic infections, gastrointestinal (GI) irritability, leukopenia, and ILD. Female patients of child bearing age should have pregnancy test prior to initiation.

Cyclosporine: typical mean daily dose is 3.5 mg/kg. Dosing adjusted to serum trough of 100-200. Side effects include hepatotoxicity, renal toxicity, BM toxicity, and myopathy.

Rituximab: Monoclonal antibody directed against CD20+ B cells. Optimal dosing has not been established, though 750 mg/m2 once weekly for two weeks has been used in the largest trial. Side effects include severe infections, infusion reactions, and nephrotoxicity.

Cyclophosphamide: 0.8-1 g/m2 monthly IV or 1.5-2 mg/kg PO daily. Side effects include BM toxicity and hepatotoxicity.

Tacrolimus: calcineurin inhibitor. Side effects include severe hepatotoxicity, renal toxicity, and BM toxicity.

IVIG: start at 2 g/kg as a monthly infusion. Effects may be seen in the first 2 weeks.

A. Renal Insufficiency.

Creatinine clearance rate (CrCl) 10-50: methotrexate dosing should be decreased by 50%, azathioprine dosing should be decreased by 25%. CrCl <10: methotrexate is contraindicated, azathioprine dosing should be decreased by 50%.

Many of the nonsteroidal immunosuppressives may cause nephrotoxicity with creatinine (Cr) monitoring warranted.

B. Liver Insufficiency.

Methotrexate is contraindicated in end stage liver disease (ESLD).

Many of the nonsteroidal immunosuppressives may cause hepatotoxicity with liver function test (LFT) monitoring warranted.

C. Systolic and Diastolic Heart Failure

Long-term steroid use or inflammatory myopathy itself may lead to heart failure. Continued monitoring for worsening of heart failure symptoms is required with potential need to switch from prednisone to non-steroidal immunosuppressive medications.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

Steroids will worsen glycemic control, and a switch to nonsteroidal immunosuppressive agents may need to occur early in the management course.

F. Malignancy

See "what diagnostic tests should be performed?" section above regarding dermatomyositis and malignancy.

G. Immunosuppression (HIV, chronic steroids, etc).

Therapeutic options all cause a degree of immunosuppression and BM toxicity. Careful evaluation for infectious complications should occur. Furthermore, long-term immunosuppression may increase the risk of lymphoma and certain other malignancies.

H. Primary Lung Disease (COPD, Asthma, ILD)

Patients with pre-existing lung conditions should likely not be treated with methotrexate and mycophenalate or at least have their pulmonary status closely monitored during treatment. Patients with ILD as a result of dermatomyositis, polymyositis or inclusion body myositis are typically treated more aggressively and may be treated with cyclophosphamide or tacrolimus earlier in their course.

I. Gastrointestinal or Nutrition Issues

Esophageal involvement may need separate treatment with dilation procedures or botulin toxin injections.

J. Hematologic or Coagulation Issues

Therapeutic options all cause a degree of immunosuppression and bone marrow toxicity. Careful evaluation for bleeding and infectious complications should occur.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

A. Sign-out considerations While Hospitalized.

Patients with inflammatory myopathies are prone to develop extramuscular complications including cardiac, pulmonary, and esophageal problems.

If called to evaluate these patients for shortness of breath, evaluate for aspiration with chest x-ray and potentially place on telemetry given the risk of development of arrhythmias.

B. Anticipated Length of Stay.

Variable depending on disease severity on admission.

C. When is the Patient Ready for Discharge.

Patients requiring hospitalization typically have severe disease either solely as a result of the extent of muscle weakness or because of pulmonary, cardiac, or GI manifestations. Since treatment initiation typically yields results in the order of weeks to months, some patients may require skilled nursing facility (SNF) placement for continued rehabilitation. If patients present with heart failure or pulmonary complications, they are ready for discharge once those conditions have stabilized.


Patients should follow up with their rheumatologist within the first one or two weeks after discharge.


Patients starting rituximab should have hepatitis B serologies prior to initiation of therapy.

Female patients of child bearing age should have a pregnancy test checked before initiation of mycophenalate.


Patients on methotrexate and cyclosporine require frequent CBC, Cr and LFT checks.

Patients on azathioprine require frequent CBC and LFT checks.

Patients on cyclophosphamide, mycophenalate and cyclosporine require frequent CBC and Cr checks.

Patients on rituximab should have a CBC checked prior to every cycle.

Patients on tacrolimus require frequent Cr and K+ checks.

E. Placement Considerations.

Patients with inflammatory myopathy severe enough to require hospital admission will likely require disposition to SNF for further rehabilitation.

F. Prognosis and Patient Counseling.

Both polymyositis and dermatomyositis have 1, 5, and 10-year survival rates of approximately 93%, 86%, and 78%, respectively. Deaths are primarily due to cardiac and pulmonary complications, followed by infection and malignancy. Dermatomyositis tends to respond better to treatment than polymyositis but is unfortunately also associated with an increased risk of malignancy. Inclusion body myositis tends to be progressive with no response to most treatment modalities.

A. Core Indicator Standards and Documentation.


B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients with esophageal involvement should have a swallowing assessment performed during their hospitalization and may require soft mechanical diet on discharge.

Patients initiated on steroids or nonsteroidal immunosuppressants should follow up with their provider immediately if they notice fever, chills, nausea, new onset edema, cough, or shortness of breath.


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