The ideal of every patient and physician is to identify a diagnosis whose natural history is self-limited, or if not, a diagnosis for which an effective treatment can be administered. Autoimmunity is believed to be the contributing, if not causal, mechanism of a significant number of neuromuscular disorders.1 Accordingly, patients with proven or suspected autoimmune neuromuscular disorders become candidates for treatments that modulate or suppress immune-mediated nerve, neuromuscular junction, or muscle dysfunction or injury. Familiarity with drugs or other interventions that suppress or modulate the patient’s immune system is therefore a prerequisite for anyone practicing neuromuscular medicine.
In this book, we will define immunomodulation as any therapy that affects in any way the native activities of a patient’s immune system in an attempt to mitigate disease. We will define immunosuppression as a subcategory of immunomodulation in which a patient’s immunologic response is impaired by one of the three recognized mechanisms.2,3 One mechanism, as occurs with drugs such as azathioprine, cyclophosphamide, mycophenolate, and methotrexate, curtails B-cell and T-cell proliferation by cell cycle interruption. Another mechanism, as exemplified by drugs such as the calcineurin inhibitors (e.g., cyclosporine and tacrolimus) and corticosteroids, is impairment of T-cell activation. A final mechanism of immunosuppression is accomplished by monoclonal antibodies–directed cell surface antigens, rituximab being the most notable example. Conversely, we will consider interventions such as intravenous immunoglobulin (IVIg) or plasma exchange (PLEX) to be immunomodulating, not immunosuppressive.
The authors strongly endorse the concept of evidence-based medicine. At the same time, we recognize that evidence-based medicine applies to populations and that strict adherence to evidence guidance is not always in the best interests of the individual patients we are responsible for. In neuromuscular medicine, there are numerous examples of treatments that are universally considered to be efficacious yet remain of unproven benefit by “evidence-based” standards.4 Corticosteroids in myasthenia gravis (MG) is one notable example, discovered by innovative effort by individual clinicians. Because of the accepted efficacy of this and other historically identified empiric treatments, it is unlikely that a number of currently accepted treatments will ever be validated by large prospective studies.
Our position is also supported by personal witness of unequivocal benefit to individual patients, who respond to treatments demonstrated to be ineffective to larger populations with the same disease. Rituximab in MuSK-positive MG is such an example.5 Accordingly, this chapter will describe, and in some cases endorse, the off-label uses of immunomodulating treatments for various neuromuscular diseases even in the absence of evidence-based support. We do so cautiously as we recognize that these idiosyncratic responses may be harmful as well as helpful. Ultimately, each physician needs, along with their patient, to determine whether the potential benefits of immunomodulating treatment, of proven or unproven benefit, exceed the probability and magnitude of potential risk.
This chapter will approach immunomodulating treatment of presumed immune-mediated disorders by focusing on the treatments, rather than the disorders themselves which will be the subject matter of subsequent chapters. A summary of these agents, and the disorders for which they may or may not be effective are summarized in Table 4-1. Details regarding dosing, side effect profiles, and recommended screening procedures are summarized in Table 4-2.
|Treatment||Disorders with Evidence-Based Efficacy||Disorders with Evidence Based or Other Reports of Inefficacy||Disorders with Supportive But Inconclusive Studies||Disorders with Anecdotal Reports of Benefit|
|Interferon β 1a||MMN54,302|
GBS (adult and pediatric) 305
|Prednisone||Oral||0.75–1.5 mg/kg/day to start||Hypertension, increased appetite, fluid and weight gain, insomnia, hyperglycemia, hypokalemia, cataracts, gastric irritation, osteoporosis, infection, aseptic femoral necrosis, myopathy, ecchymosis, change in body habitus and facial appearance||Weight, blood pressure, serum glucose/potassium, cataract formation|
|Methylprednisolone||Intravenous||1 g in 100 mL/normal saline over 1–2 hours, daily or every other day for 3–6 doses||Arrhythmia, flushing, dysgeusia, anxiety, insomnia, fluid and weight gain, hyperglycemia, hypokalemia, infection||Heart rate, blood pressure, serum glucose/potassium|
|Azathioprine||Oral||2–3 mg/kg/day; single AM dose||Flu-like illness, hepatotoxicity, pancreatitis, leukopenia, macrocytosis, neoplasia, infection, teratogenicity||Blood count, liver enzymes|
|Methotrexate||Oral||7.5–25 mg weekly, single or divided doses; 1-2 day a week dosing||Hepatotoxicity, pulmonary fibrosis, infection, neoplasia, infertility, leukopenia, alopecia, GI irritation with nausea/diarrhea, stomatitis, teratogenicity||Liver enzymes, blood count, chest x-ray baseline and yearly|
|Subcutaneously||20–50 mg weekly; 1 day a week dosing||Same as oral||Same as p.o.|
1.5–2 mg/kg/day; single AM dose
0.5–1.0 g/m2 per month × 6–12 months
|Bone marrow suppression, infertility, hemorrhagic cystitis, alopecia, infections, neoplasia, teratogenicity||Blood count, urinalysis|
|Cyclosporine||Oral||4–6 mg/kg/day, split into two daily doses||Nephrotoxicity, hypertension, infection, hepatotoxicity, hirsutism, tremor, gum hyperplasia, teratogenicity||Blood pressure, creatinine/BUN, liver enzymes, cyclosporine levels|
|Tacrolimus||Oral||0.1–0.2 mg/kg/day in two divided doses||Nephrotoxicity, hypertension, infection, hepatotoxicity, hirsutism, tremor, gum hyperplasia, teratogenicity, hyperglycemia||Blood pressure, creatinine/BUN, liver enzymes, tacrolimus levels|
Adults (1 gBID to 1.5 g BID)
Children (600 mg/m2/dose BID (no more than 1 g/day in patients with renal failure)
|Bone marrow suppression, hypertension, tremor, diarrhea, nausea, vomiting, headache, sinusitis, confusion, amblyopia, cough, teratogenicity, infection, neoplasia, PML||Blood count|
|Intravenous Immunoglobulin||Intravenous||2 g/kg over 2–5 days; then 1 g/kg every 4–8 weeks as needed||Hypotension, arrhythmia, diaphoresis, flushing, nephrotoxicity, headache, aseptic meningitis, anaphylaxis, stroke||Heart rate, blood pressure, creatinine/BUN|
|Some check B-cell count prior to subsequent courses (but this may not be warranted)|
Before initiating immunomodulating therapy, it is critical to consider the probability and magnitude of both the potential risk to an individual patient, as well as the potential benefit. There is a consensus that patients who receive immunomodulating treatment are at an increased risk for both infection and malignancy.6 There is also a consensus that the risk is probably dependent on numerous variables including the genetics and comorbidities of the individual patient, the agent or agents used, as well as cumulative dose and duration of treatment. The following section will review some of these considerations facing clinicians and their patients who are contemplating immunomodulating treatment. On discussing risk with patients, we find it useful to utilize the World Health Organization guidelines which define risk as very common >1/10, common >1/100, uncommon >1/1,000, rare >1/10,000, and very rare >1/100,000.7
In consideration of immunomodulating treatment, it is important to be armed with knowledge relevant to a number of key issues in order to make rational treatment decisions. Of primary importance is the identification of an objective parameter to measure. A pretreatment baseline should be established in order to determine whether treatment is effective or not in the future. The ideal parameter(s) chosen should be not only quantifiable and reproducible, it (they) should correlate with meaningful improvements in patient comfort and function.
In neuromuscular disease, measurements of strength are the most commonly utilized. We have found manual muscle strength testing and handheld dynamometry (e.g., microFET2®) to be helpful in this regard, along with quantitative bedside assessments of sensation (e.g., timed vibration or the Rydel-Seiffer® tuning fork). There are many functional or symptomatic scales that have been developed for specific diseases, e.g. ALS, myasthenia, and peripheral neuropathy, that also facilitate determination of treatment response.8–13 Unfortunately in neuromuscular disease, other biomarkers such as imaging, electromyography and nerve conduction study data, and measurement of serologic markers are not always accurate or practical means of monitoring treatment response.
A master clinician understands the natural history of the disease they are treating as well as the properties of the agents they are using. The latency between treatment and response is dependent on at least two parameters, the pharmacology of the immunomodulating agents used and the pathophysiology of the disease. For example, morbidity created by disorders that impede ion channel function, demyelinate axons without otherwise injuring them, or that injure relatively easily repairable components of the neuromuscular system such as ACh receptors may be expected to respond to an effective treatment relatively rapidly, within days to weeks in many cases. Conversely, disorders that require axon regrowth may require months before return of function becomes evident depending on the number of axons injured, the distance between the site of injury and the muscle(s) that require(s) reinnervation. Lastly, disorders that lead to significant destruction of motor or sensory cell bodies are limited in their ability to recover as their regeneration is unlikely, even if an effective treatment is initiated.
Furthermore, it is important to be familiar with the duration of treatment benefit as well as the latency between therapeutic intervention and clinical response. Without an appreciation of both, at least three potential risks may be encountered. A clinician may give up on a treatment before it has had a chance to work, and by doing so, initiate a second, potentially unnecessary and harmful agent. Conversely, a clinician may be overly optimistic, waiting too long for an ineffective agent to work, thus delaying exposure to an additional, potentially beneficial treatment. In addition, a clinician may unnecessarily procrastinate by waiting too long to initiate subsequent maintenance doses, allowing potentially avoidable relapses to occur and by doing so, eroding a patient’s confidence in their physician.
A particularly vexing problem in this age of evidence-based medicine is the patient with a suspected or proven autoimmune disorder for which no known proven treatments exist. In these cases, a diagnostic and potentially therapeutic trial may be undertaken. IVIg is frequently used for this purpose both for its relatively rapid onset of action, its efficacy in many autoimmune diseases, and in consideration of its relative safety. For example, although current evidence does not support the routine use of IVIg in lower motor neuron syndromes, some of these patients are thought to represent cases of multifocal motor neuropathy (MMN) without demonstrable biomarkers such as elevated GM1 autoantibody titres or conduction block.14,15 In this and other comparable situations, we follow the lead of others by typically providing a 3-month therapeutic trial of IVIg.14,16 Although this practice may be considered somewhat arbitrary in its duration, it represents in our mind a reasonable compromise between a sufficient interval to detect benefit in this demyelinating neuropathy and the waste of an expensive resource. In the case of an MMN suspect, unequivocal stabilization would provide sufficient proof of treatment efficacy as this would differ from the inexorable progression of motor neuron disease which is the primary differential diagnostic consideration.14
Immunomodulating treatment strategies vary in consideration with the treatment modality employed, individual disease characteristics, and individual patient context. There are general principles however, that include the recognition of maximal achievable benefit with the goal of avoiding excessive treatment. If disease remission can be achieved, with the potential in that particular disorder for a durable, treatment-free response, an attempt should be made to wean by reducing the amount and/or frequency of administration. For example, it is not uncommon for patients with vasculitic neuropathies who respond to immunosuppression to eventually be successfully weaned from treatment after 2–3 years and enjoy years of subsequent treatment-free stability. The goal with any patient, is to ensure, through clinical or when relevant other means, continued patient improvement or stabilization. At the same time, the goal is to also limit potential adverse effects and costs of chronic treatment while at the same time achieve and sustain the best potential outcome.
These differing treatment strategies are illustrated in the following examples. Corticosteroids in MG or inflammatory myopathies or IVIg in MMN are often initiated at high “induction” doses and then gradually weaned in an attempt to identify the smallest dose or longest interval between treatments that will achieve remission or maintain an acceptable level of morbidity. Conversely, with IVIg in Guillain–Barré syndrome (GBS) or rituximab in MG, a singular prescribed course is initially delivered regardless of initial response and repeated in the future only with initial response and subsequent relapse.
RISK CONSIDERATIONS WITH IMMUNOMODULATING TREATMENTS
Pneumocystis jirovecii, formerly known as Pneumocystis carinii (PCP), is a fungal interstitial pneumonia that occurs predominantly in individuals who are immunosuppressed as a result of their disease or its treatment.17 It is widely accepted that 70–90% of patients who acquire PCP have received corticosteroid treatment.18 PCP prophylaxis advocates justify its use in immunosuppressed individuals due to the potential morbidity and mortality associated infection. The mortality risk is estimated to be 30–50%, even if recognized and treated.18
The onset of PCP may be subacute or indolent. Typical symptoms are dyspnea on exertion, nonproductive cough, fever, and tachycardia. Diagnosis is supported by imaging evidence of bilateral pulmonary infiltrates extending outward from the perihilar regions and an elevated serum LDH. Confirmation typically requires bronchoalveolar lavage.
Prophylaxis is preferentially achieved with trimethoprim–sulfamethoxazole, 160–800 mg/day or double strength three times a week.19 Either regimen is felt to be 90% successful in preventing PCP. In those intolerant of sulfa, atovaquone, dapsone, and pentamidine represent alternatives. For those who favor PCP prophylaxis, current recommendations suggest it should be introduced if prednisone is utilized at a dose greater than 20 mg/day for a duration that exceeds 4 weeks.
PCP prophylaxis in neuromuscular patients treated with immunomodulating agents is not practiced universally. The evidence basis for PCP prophylaxis is largely derived from cancer and pulmonary patient populations.18 In addition, there is a paucity of information to guide clinicians regarding adjusted risk based on the number and types of agents utilized, their doses, and the duration of exposure. Although the severity of PCP infection is unquestioned, its frequency in neuromuscular patients treated with immunomodulating agents is less well known. Although many disciplines such as rheumatology and infectious disease seem to favor its use, neurologists appear to be in general less sanguine about prophylactic necessity. For example, a recent poll neuromuscular specialists posted on Rick’s Real Neuromuscular Friends indicated that 53% of 45 respondents do not provide routine PCP prophylaxis in this population.20 Many have never seen a case of PCP despite having treated many patients chronically with one or more immunomodulating agents generating a more conservative perspective than suggested above.
The risk of tuberculosis reactivation is considered to be approximately three to six times greater in patients receiving tumor necrosis factor (TNF) inhibitors and corticosteroids.21 It becomes prudent therefore to ascertain the risk of latent tuberculosis infection (LTBI) in any individual in whom immunomodulating treatment is considered. Screening would include determining risk of prior, chest x-ray, and in those who are at risk, either tuberculin skin testing (TST) or an interferon (IFN) gamma release assay (IGRA). TST is thought to be 98% sensitive in detecting LTBI. Its limitations are that it may not detect infection in the first 8 weeks following exposure, may be falsely negative in individuals already immunocompromised, or may be falsely positive in individuals who have received prior BCG vaccination. IGRAs are complementary diagnostic tools for LTBI. They are in vitro blood tests of cell-mediated immune response to Mycobacterium tuberculosis and measure T-cell release of IFN-gamma following stimulation by antigens specific to M. tuberculosis. The two available IGRAs are QuantiFERON-TB Gold In-Tube and the T-SPOT.TB. They are the preferred means to confirm LTBI in individuals with prior BCG exposure. The IGRAs appear to be somewhat more specific and less sensitive for predicting future active TB than the tuberculin skin test but the differences are modest. Like TST, IGRA false negatives are more likely to occur in immunosuppressed individuals. Both IGRAs and the TST have high negative predictive values for development of future infection.21
Like all clinical decisions, prophylactic treatment of patients suspected of LBTI needs to consider the relative benefits and risks. Currently, someone with suspected LBTI who is going to receive immunosuppressant treatment with corticosteroids, TNF-α inhibitors and probably other agents, is recommended to receive prophylactic treatment with isoniazid (with pyridoxine), rifampin, or a combination of both. Isoniazid is typically prescribed as 300 mg daily for 9 months or 900 mg twice a week for 6 months. Rifampin alone is dosed at 600 mg/day for 4 months. When both drugs are used together, 600 mg of rifampin and 300 mg of isoniazid are given daily for 3 months.21 Other considerations are the risk of isoniazid hepatotoxicity which increases with age and exposure to other hepatotoxic agents and the numerous drug interactions that occur with rifampin use.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating central nervous system disorder caused by infection with the John Cunningham (JC) virus. The JC virus is ubiquitous, found in 50–60% of the normal population and is typically sequestered in peripheral organs.22 PML is a disorder seen almost exclusively in the immunosuppressed. Even in this population, the virus rarely gains access to the central nervous system.
To date, PML has been associated with two agents employed in immune-mediated neuromuscular disorders, rituximab and mycophenolate mofetil (MMF).23 Infliximab, etanercept, and alemtuzumab, have also been reported as PML risk factors as have other currently available monoclonal antibodies that may be employed in the treatment of neuromuscular disease in the future.24 Undoubtedly, it will be described in association with other immunomodulating agents relevant to neuromuscular disease in the future. The risk for PML appears to be predominantly in those who harbor the JC virus prior to the introduction of immunosuppressant treatment.
Surveillance and treatment paradigms have been developed for PML in multiple sclerosis patients exposed to natalizumab.22 Presumably as the risk of developing PML with the immunosuppressant drugs described in this chapter is thought to be very rare, we are unaware of any recommendations for JC virus surveillance and prophylaxis for any agents described in this chapter. As anticipated, recognition of PML in any patient receiving immunosuppressant drugs warrants drug discontinuation in virtually any clinical context.
Stongyloidiasis is a parasite that is endemic in warm moist tropical and subtropical climates such as Eastern Europe, South and Southeast Asia, Central America, South America, and sub-Saharan Africa.25–27 It is transmitted via skin penetration by infective filariform larvae following exposure to water or soil contaminated by human or canine fecal material. The larvae are hematogenously carried to the lungs, regurgitated, and then swallowed where they mature into adults in the intestines.25 The reproductive cycle of the nematode and resultant reinfection may continue indefinitely. The autoinfected human host frequently remains asymptomatic or experiences mild nonspecific skin and gastrointestinal symptoms.25,26 This equilibrium may persist indefinitely.
Immunosuppression however, particularly with corticosteroids, may result in multiorgan dissemination and hyperinfection.25,26 Control of parasitic infections requires Th2 cytokine, eosinophilic, and IgE influence, all of which are suppressed by steroids and other immunomodulating agents.25,26 With hyperinfection, mortality is estimated to be 60–85%.27 For this reason, parasitic and serologic surveillance is recommended for anyone at increased risk prior to immunomodulating treatment. The absence of hypereosinophilia occurs frequently in infected individuals and does not represent a sensitive screening test. Ideally, patients at risk should undergo three negative surveillance stool specimens and an ELISA screening test for IgG Strongyloides stercoralis antibodies available through the Centers for Disease Control before treatment is begun.25,26 The ELISA test is thought to be 80–100% sensitive and highly specific in immunocompetent individuals. Its sensitivity drops significantly in immunosuppressed individuals. A negative test needs to be interpreted cautiously in individuals already exposed to immunomodulating treatment.25 If infected, ivermectin, thiabendazole, and albendazole are the most commonly used therapeutic agents.26,27 One suggested regimen for strongyloidiasis prophylaxis would be ivermectin 200 μg/kg/day for 2 days, repeated within 2 weeks.26
Questions regarding vaccination of patients in whom immunomodulating treatment is being considered or is already being received are very relevant to the practice of neuromuscular medicine. Current recommendations hold that ideally, patients should be vaccinated against influenza, pneumococcus, tetanus, hepatitis A and perhaps B prior to initiation of immunosuppression.28 Once immunosuppression has commenced, there appears to be a consensus that vaccines containing dead virus can be utilized without undue risk but that live-virus vaccines should be avoided.6
Management of immunomodulating treatment in women of child-bearing age is difficult. Current evidence holds that use of corticosteroids or IVIg provides no additional risk for mother or child during pregnancy.7,29 We are very reticent to use other immunomodulating agents in childhood unless patient morbidity provides no other options. If corticosteroids are used before full growth is achieved, it is recommended that linear growth be tested regularly and growth hormone treatment considered if necessary.7
Patients who receive immunosuppressive therapy are believed to be at increased risk of developing malignancy.28 This risk is attributed to oncogenic infectious agents, reduced immune surveillance of cells having undergone mutation in relationship to age or environmental factors, or direct effects on oncogenes.30 Notable oncogenic organisms whose proliferation may be aided by immunosuppression include Epstein–Barr virus, human herpesvirus 8, human papillomavirus, hepatitis B and C, and helicobacter. The malignancies most commonly associated with immunosuppression include lymphoproliferative disorders, Kaposi’s sarcoma, as well as anogenital, liver, and stomach cancer.28 Data pertaining to the relative risk of developing these malignancies, indexed to the numbers, types, and length of exposure to immunosuppressant medications are lacking although it is widely accepted that both increased dose and duration of exposure are relevant.30 Of interest, available data suggests that cancer risk rapidly dissipates following discontinuation of immunomodulating treatment.28 The pragmatic benefit of this knowledge is uncertain given the presumption that discontinuation of an effective immunosuppressive agent is unlikely unless cancer develops. Recommendations regarding rational, evidence-based cancer surveillance protocols for patients on immunomodulating treatments are elusive and are beyond the scope of this text. Discussion of this risk should nonetheless be part of the informed consent process. Consideration of dose reduction and potentially discontinuation is recommended in those who achieve complete disease remission.
There also appears to be an increased risk of skin cancers in patients receiving immunosuppressant drugs. The incidence of squamous cell carcinoma is believed to be increased by 14–82 fold and malignant melanoma increased by a factor of 2.4 in the solid organ transplant population.31 We routinely advise patients on immunosuppressant drugs of the increased skin cancer risk and recommend limiting sun exposure, ample use of sun-blocking agents, and routine skin surveillance.
INDIVIDUAL TREATMENTS MODALITIES
In the following section, individual immunomodulating treatments commonly used in neuromuscular disease will be discussed. Consideration of mechanisms of action, specific disorders in which individual agents are often used, adverse effects and management strategies will be addressed for each modality. For more detailed management strategies, the reader is referred to the relevant chapter on the disease in question.
Alemtuzumab is a monoclonal antibody directed against the CD52 antigen found on the cell surface of mature lymphocytes. It is used primarily in the treatment of chronic lymphocytic leukemia, cutaneous and other T-cell lymphomas. There has been limited experience with its use in neuromuscular disorders.
Seven chronic inflammatory demyelinating polyneuropathy (CIDP) patients who have received alemtuzumab have been reported to demonstrate some degree of efficacy.32,33 An open-label multicenter trial of alemtuzumab in CIDP is underway.34
Some patients receiving alemtuzumab have been reported to develop autoimmune disease, most notably Graves disease and hemolytic anemia.34
One reported protocol consists of five daily intravenous infusions of 30 mg with repeated courses as required.34
Azathioprine is a purine analog that acts as a cytotoxic immunosuppressive agent.35 Its main active metabolite, 6-mercaptopurine, is a purine antagonist.36 It is a cell-cycle–specific inhibitor, exerting its actions mainly in the resting (G1) and DNA synthesis (S) phases of the cell cycle through suppression of GTPase Rac1 activation.2 Although its primary effects are directed at T cells, it is efficacious in T-cell–dependent antibody-mediated disorders such as MG.1 In addition to reducing numbers of circulating T cells, it also reduces levels of B-cell–derived immunoglobulins and interleukin-2 (IL-2).
Azathioprine is a commonly used maintenance, “steroid-sparing” therapy in MG. Several trials have demonstrated the efficacy of azathioprine alone or in combination with prednisone.37–42 Improvement is noted in 70–90% of patients with myasthenia treated with azathioprine, including some patients who are steroid resistant.43 We commonly initiate azathioprine (or other steroid-sparing agent) along with corticosteroids in any myasthenic patient with generalized disease in whom we anticipate the need for long-term immunomodulating treatment. We do so in the hope of facilitating steroid weaning, thereby limiting risk of long-term steroid side effects. By starting early, we take advantage of the short-term benefits of corticosteroids, recognizing the delayed therapeutic latency (3–15 months) of azathioprine which may require up to 2 years to achieve full effect.1,44
Azathioprine is also used a second-line agent in a number of presumed immune-mediated neuromuscular diseases, either as an adjunct to steroids, as a long-term maintenance agent. On occasion, it may become a first-line agent when more typical first-line agents (e.g., corticosteroids, IVIg, or PLEX) have failed. For the most part, the use of azathioprine in nonmyasthenic NM diseases is based on expert opinion or small case series. It has been used in dermatomyositis, polymyositis, CIDP, MMN, Lambert–Eaton myasthenic syndrome (LEMS), distal acquired demyelinating sensory neuropathy (DADS) vasculitic neuropathy, diabetic lumbosacral radiculoplexus neuropathy, Isaac’s syndrome, and sarcoidosis.34,35,45–55,56 We would advocate for its use in dermatomyositis, polymyositis, CIDP, LEMS, and sarcoid neuropathy in a patient with significant morbidity, who responds to first-line treatment, but who experiences unacceptable side effects or other impediments to long-term treatment with more conventional first-line treatments for these disorders.
Side effects have been reported in 35–42% of individuals. Fortunately, they are often mild and tolerable. They typically, although not invariably, develop within days to weeks of drug exposure. Many individuals tolerate the drug without any apparent side effects for protracted periods of time, which along with its potential effectiveness, make it an attractive agent. 35,40 A systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurs in 12% of patients requiring discontinuation of the drug. As mentioned, this reaction generally occurs within the first few weeks of therapy and resolves within a few days of discontinuing the azathioprine. Rechallenge with azathioprine may be successful but usually results in the recurrence of the systemic reaction. Other uncommon but major complications of azathioprine are bone marrow suppression, hepatic toxicity, pancreatitis, teratogenicity, risk of opportunistic infection and oncogenicity including increased risk of skin cancer.35,40
Azathioprine is available in 50 mg tablets without a parenteral analog. We typically begin with one tablet a day and escalate slowly to a maintenance dose of 2–3 mg/kg/day, typically 2.5 mg/kg/day. Prior to beginning azathioprine, we typically screen for thiopurine methyltransferase (TPMT) deficiency. Patients who are heterozygous for the TPMT mutation may be able to tolerate azathioprine at lower dosages but those who are homozygous should not receive drug. They cannot metabolize it and may experience severe bone marrow toxicity. Fortunately, the majority of patients who develop adverse hematologic responses in response to azathioprine recover fully once the drug is discontinued.
In patients receiving azathioprine, complete blood count (CBC) and liver function tests are monitored every 2 weeks until the patient is on a stable dose of azathioprine and then every 3–6 months for 2 years. After that, with stable blood counts, yearly surveillance is likely to be sufficient. If the white blood count falls below 4,000/mm3, the dose should be decreased. Azathioprine is held if the white blood count declines to 2,500/mm3 or the absolute neutrophil count falls to 1,000/mm3. Leukopenia can develop as early as 1 week or as late as 2 years after initiating azathioprine. As in most drugs with potential hepatotoxic effects, azathioprine should be discontinued if transaminases increase more than two to three times the baseline values. In the treatment of patients with myositis, it is important to determine whether transaminase elevation is due to liver damage from drug or muscle injury from disease. Accordingly, in these situations, we follow glutamyl transpeptidase levels (GGT), an enzyme present in liver but not muscle, in addition to AST and ALT for this reason. Liver toxicity from azathioprine generally develops within the first several months of treatment or increase in dosage. Leukopenia generally reverses in 1 month and hepatotoxicity can take several months to resolve.
An elevated mean corpuscular volume is an anticipated effect of azathioprine therapy and is used by some clinicians as an indicator of a biologic response. Allopurinol should be avoided in patients who require azathioprine because it interferes with azathioprine metabolism, increasing drug levels, and increasing the risk of bone marrow and liver toxicity.
Glucocorticoid effects are mediated through both genomic, nuclear glucocorticoid receptors as well as nongenomic cell surface receptors.57,58 They are one of the most versatile immunomodulating agents available in that they affect both cell-mediated and antibody-mediated autoimmunity.1 Corticosteroids largely affect T-cell function by producing T-cell apoptosis, suppressing the transcription of proinflammatory cytokines and impairing dendritic cell maturation.36 Specifically, glucocorticoids increase the rate of lipocortin synthesis which promotes anti-inflammatory effects by inhibition of phospholipase A2 as well as the proinflammatory cytokines IL-1, IL-2, the IL-2 receptor, INF gamma, and TNF.
The use of corticosteroids in autoimmune MG deserves special consideration. The recognition that corticosteroids were beneficial to patients with MG was historically delayed by the initial disease worsening that occurs in approximately 30% of patients receiving high-dose steroids, typically beginning between week 1–3 and lasting approximately 1 week.43,59–62 The mechanism of the worsening appears to be unique to disorders of neuromuscular transmission, apparently secondary to weak neuromuscular blocking properties of the drug supported by the demonstration of decremental responses to slow repetitive stimulation.61
Fortunately, the benefits of corticosteroids in MG became subsequently recognized. They remain a mainstay of MG treatment despite the lack of evidence-based support for its use. Corticosteroids, typically prednisone, are the first-line drug in anyone whose disease severity requires immunomodulating therapy unless other confounding clinical variables coexist.43 Its efficacy in MG appears to be universally accepted, making it unlikely that enrollment in a placebo-controlled trial would ever succeed.
Seventy-five percent of myasthenics are estimated to improve with corticosteroid use, 30% achieving remission and 45% marked improvement.36 Improvement may become evident within 2 weeks of initiation of high dose (0.75–1.5 mg/kg) daily dosing and is typically well established by 6–8 weeks. Absence of a significant response within 4 weeks suggests treatment failure and should prompt consideration of alternative or additional treatments. There have been reports of myasthenics who appear resistant to both the adverse and beneficial effects of prednisone who respond well to prednisolone.36
In patients in crisis who are intubated, parenteral methylprednisolone may be prescribed at doses of up to 1 g/day for up to 7 days before tapering to a 60–100 mg/day prednisone equivalent. In these patients, the risk of crisis provoked by steroids becomes largely irrelevant.63 In someone with significant morbidity from generalized disease, who we do not feel is in imminent danger of crisis, and in whom we are confident that adequate monitoring can occur, we may initiate high-dose prednisone, typically at 1–1.5 mg/kg up to 100 mg/day. In others whose morbidity warrants immunomodulating treatment, but where neither disease severity or risk of crisis warrants initial high-dose treatment, we utilize the so-called “start low, go slow” approach beginning at 10 or 20 mg of prednisone per day and gradually increasing by 5–10 mg/day every week or two until the target dose of 50–100 mg/day is reached.
Corticosteroids are used in numerous other presumed immune-mediated neuromuscular disorders including a number of neuropathy syndromes. The best evidence for efficacy exists in classic CIDP with a phenotype of generalized symmetric weakness, sensory signs and symptoms, and areflexia.34,59,64–68 Steroids also appear to be effective for the presumed CIDP variant, multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), (a.k.a. Lewis–Sumner syndrome).65,69,70 Steroids have less apparent efficacy with other presumed CIDP variants, particularly when they are pure sensory or pure motor.65 Although prednisone is the most commonly used glucocorticoid for CIDP, successful intravenous methylprednisolone and oral dexamethasone regimens have been reported as well.71,72
The weight of existing evidence suggests that steroids provide no benefit and may be harmful in the aggregate in GBS, MMN, and DADS associated with IgM monoclonal proteins, or other neuropathies associated with monoclonal gammopathy of unknown significance.65,73–77
Corticosteroids are also considered to be effective in some but not all inflammatory myopathies.45,59 They are commonly used as a first-line treatment based on expert opinion in dermatomyositis, polymyositis, and immune-mediated necrotizing myopathy/myositis but are considered ineffective in inclusion body myositis.56,78,79
There is little doubt that immunomodulating treatment favorably alters the natural history of the systemic vasculitides. Corticosteroids, often with concomitant cyclophosphamide or rituximab are the backbones of treatment for these disorders.47,56,80–82 There is considerable support for the use of corticosteroids in the treatment of sarcoidosis and sarcoid neuropathy but no evidence-based confirmation. 83,84 There is a dearth of evidence in support of corticosteroid use in brachial plexus neuritis.84 We are of the opinion that steroids may benefit the painful aspects of this disorder if prescribed early but they appear to have a limited, if any, benefit in altering the natural history of the disease. Corticosteroids have been used with anecdotal reports or reports based on expert opinion of benefit in stiff person syndrome and diabetic lumbosacral radiculoplexus neuropathy.85
It is estimated that at least 30% of patients will experience corticosteroid-induced side effects, dependent upon dose and duration of therapy.36 Once a desired therapeutic effect is achieved, an attempt is made to wean to the lowest effective maintenance dose with 20 mg/day considered an acceptable balance between the benefits and drawbacks of long-term steroid side effects.36 Adverse effects of corticosteroids are largely dose-dependent and include diabetes, hypertension, peptic ulcer disease, osteopenia, cataracts, glaucoma, opportunistic infections, dyslipidemia, hypokalemia, increased appetite and weight gain, insomnia, and myopathy.59,62 Steroid psychosis and aseptic necrosis appear to be adverse effects that are idiosyncratic in nature. Interventions intended to prophylax against these complications will be addressed in the management considerations section below.
Corticosteroids are frequently administered in a single daily morning dose to parallel the normal circadian peak of endogenous cortisol production.1,59 Therapeutically, this strategy has been demonstrated to have some advantage in patients with rheumatoid arthritis although interpretation may be somewhat confounded by relief of morning stiffness, a notable source of morbidity in this disease.7
Once maximal efficacy has been achieved, we attempt to wean to the smallest effective maintenance dose and typically do so in an every other day format.1,59,86 We have utilized two different strategies. One is to begin the weaning process by initially doubling the induction dose on odd days and alternating this with zero on even days while beginning to reduce the aggregate dose. For example, a patient with an induction dose of 60 mg/day would be switched to 110 mg alternating with zero on any every other day basis. The alternative strategy is to initiate the weaning process by subtracting from the odd day dosage while maintaining the even dosage, for example, 60 mg on even days, 50 mg on odd days.
The speed of weaning proceeds based on individual patient context. For example, development of significant steroid side effects such as myopathy will accelerate the weaning pace whereas any indication of disease exacerbation may put the weaning process on hold. As a general guideline, we reduce the dose by 10 mg every 2 weeks. With the first regimen, this would mean 100 mg alternating with zero. With the second regimen this would mean 60 mg alternating with 40 mg. Once a dose of 20 mg every other day is reached, we taper more slowly, typically in increments of 2 mg every 2–4 weeks based on clinical response and the potential development of signs and symptoms of potential adrenal insufficiency.
Tuberculosis, strongyloidiasis, and herpes zoster are the three infectious agents we are aware of where corticosteroids may fulminantly exacerbate pre-existing, indolent infection. Consideration may be given to shingles vaccination prior to steroid initiation in individuals. It is estimated that it is safe to administer steroids or other immunomodulating agents 2 weeks or more after administration of this or any other live virus.28 We routinely question patients for potential exposure to tuberculosis and when in doubt perform PPD, chest x-ray, and IGRA testing. If there is suggestion for indolent TB infection, and immunomodulating treatment is medically necessary, we initiate isoniazid and pyridoxine treatment concomitantly unless otherwise contraindicated. If the patient comes from an area where strongyloidiasis is endemic, we consider baseline serologic testing and stool analysis.
Patients on long-term corticosteroids should receive baseline screening and periodic monitoring of intraocular pressure, blood pressure, blood sugar, lipids, and bone density. In particular, glucocorticoids facilitate osteopenia by interfering with bone formation through apoptosis of osteocytes and enhancing bone resorption through inhibition of osteoprotegerin, an endogenous antiresorptive cytokine.87 In any patient who will be receiving corticosteroids for more than 3 months, it is prudent to obtain a bone density and initiate daily treatment with 2,000 IU of vitamin D3 and 1,000 mg of calcium, promote exercise and suggest no more than modest alcohol intake.87–89 In men >50, women who are postmenopausal, or anyone with a T score of −1.5 or below, initiation of a bisphosphonate such as alendronate at a dose of 10 mg daily or 70 mg weekly, or 35 mg three times a week is recommended.87,90
We do not routinely recommend gastric protection in patients using chronic corticosteroids unless they are symptomatic or at increased risk for gastritis because of concomitant use of nonsteroidal anti-inflammatory agents. In these situations, prophylactic treatment with a proton pump inhibitor, misoprostol, or a cyclooxygenase 2 inhibitor is utilized.7 In addition, patients are instructed to start a low-sodium, low-carbohydrate, high-protein diet to prevent excessive weight gain and in the case of a high-protein diet, to theoretically reduce the risk of steroid myopathy. Patients are also encouraged to slowly begin an aerobic exercise program as it is hypothesized that both osteopenia and steroid myopathy are enhanced by immobility. Lastly, augmentation of corticosteroid dosing should be considered perioperatively in order to avoid risk of adrenal insufficiency in any patient who has been receiving these drugs for more than a month.7