Clinical features and immunopathogenesis

The neuromuscular disorders treated with immunotherapies encompass a large and heterogeneous group of diseases, including the inflammatory neuropathies, neuromuscular junction diseases, and inflammatory myopathies.

The inflammatory neuropathies are characterized by a broad spectrum of disorders and include chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, chronic immune sensory polyradiculopathy, paraproteinemic polyneuropathies, and nodal and paranodal neuropathies. Their inclusion in this category is due to the presence of inflammation seen on nerve biopsy and their response to immunosuppressant or immunomodulatory treatments. Vasculitic neuropathies and Guillain-Barré syndrome are often included in this category but are out of the scope of this article. Although they share some clinical and electrophysiological features, the inflammatory neuropathies differ in their presentation, immunopathogenesis, response to treatment, and outcome.

Chronic inflammatory demyelinating polyradiculoneuropathy. CIDP is characterized by weakness, sensory loss, and areflexia and presents with a relapsing-remitting or chronic progressive course (for more information, see the Chronic inflammatory demyelinating polyradiculoneuropathy article). It is the most common treatable chronic neuropathy worldwide, affecting up to 9 in 100,000 patients (105). Two different and complementary mechanisms have been proposed in CIDP pathogenesis. Some authors propose a role for an antibody-mediated pathogenesis supported by: (1) reports that up to 30% of patients have antibodies against myelin proteins, (2) reports that there is deposition of immunoglobulin and complement in sural nerve biopsies, and (3) therapeutic response to intravenous immunoglobulins and plasma exchange.

Other authors have found T cell and macrophage infiltration on sural nerve biopsies; this, along with data from animal models, suggests a role of cellular immunity in CIDP pathogenesis (90).

Of note, many patients diagnosed with CIDP ultimately receive an alternative diagnosis after further investigation. In a retrospective review of 37 patients who failed initial treatment with IVIG, plasma exchange (PLEX), and corticosteroids, 54% were found to have an alternative diagnosis (85). Other diseases to consider include autoimmune nodopathies; chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD); polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS, an osteosclerotic myeloma); Charcot-Marie-Tooth; hereditary neuropathy with liability to pressure palsies; and transthyretin (TTR) familial amyloid polyneuropathy.

Autoimmune nodopathies. Antibodies targeting proteins located at or around the nodes of Ranvier were discovered in a subgroup of CIDP patients and have since been proposed to be separate entity (153). These antibodies target contactin-1 (CNCT1), contactin-associated protein 1 (CASPR1), neurofascin-140 (NF140), neurofascin-155 (NF155), and neurofascin-186 (NF186). These proteins are involved in constructing and maintaining the nodes of Ranvier by clustering voltage-gated sodium channels and separating them from the voltage-gated potassium channels outside of the nodes. The antibodies are primarily of the IgG4 subclass, which cannot internalize potential antigens or activate the complement cascade, leading to a typical inflammatory response. Instead, the mechanism is thought to be blockade of protein-protein interactions inflammation, which may be why autoimmune nodopathies and paranodopathies are resistant to immunotherapy that is typically effective in treating CIDP (91).

Small series have demonstrated clinical patterns in the phenotypes of these patients. Those with anti-CNCT1 and CASPR1 have early axonal damage, predominantly motor involvement, and are typically older. Some patients with anti-CNCT1 may have an associated nephrotic syndrome (131). Those with anti-NF155 tend to be younger with distal weakness, autonomic dysfunction, and tremor of cerebellar origin (131; 47). Anti-NF140 and 186 can present with a subacute, severe sensory ataxia and may have associated cranial neuropathy and axonal loss (46). Patients with pan neurofascin antibodies against NF140, NF155, and NF186 typically present in a monophasic acute/subacute course with severe sensorimotor tetraplegia, cranial nerve involvement, and autonomic dysfunction. These patients may need mechanical ventilation, and about 30% may have an associated nephrotic syndrome (67).

Multifocal motor neuropathy. Multifocal motor neuropathy is a rare chronic motor neuropathy characterized by slow progression of distal asymmetric weakness in one or more limbs, usually the hands. Sensory function is often preserved, but some patients may complain of mild sensory disturbances. Distal muscle atrophy is frequent, and the differential diagnosis with motor neuron diseases may be difficult. Electrophysiologic studies display demyelinating features and, characteristically, conduction blocks. Up to 40% of patients have IgM antibodies against GM1 ganglioside, suggesting an autoimmune origin. Some studies suggest that these antibodies are pathogenic and can fix complement. Without treatment, multifocal motor neuropathy can lead to significant disability. Therefore, early recognition and treatment are crucial to avoid disability. For more information, see the Motor and multifocal motor neuropathies article.

Paraproteinemic neuropathies. Up to 10% of patients with a polyneuropathy of unknown origin have a monoclonal gammopathy, also called paraproteinemia (89). However, only 5% to 28% of patients with a monoclonal gammopathy are associated with a polyneuropathy. Polyneuropathies associated with monoclonal gammopathies usually develop as slowly progressive, mainly sensory-ataxic, symmetric, distal polyneuropathies and can be either axonal or demyelinating. Monoclonal gammopathies are caused by monoclonal plasma cells, which expand and secrete a relative excess of a nonfunctional immunoglobulin. Monoclonal gammopathies can be made of IgG, IgM, and IgA subclasses. IgG monoclonal gammopathies are the most frequent in the general population, but IgM monoclonal gammopathies predominate in patients with associated polyneuropathy. Fifty percent of monoclonal IgM-associated polyneuropathies have IgM antibodies against myelin-associated glycoprotein and constitute a discrete syndrome (see article on polyneuropathy associated with anti-MAG IgM antibodies). Monoclonal gammopathies may appear in the context of a hematologic neoplasm (multiple myeloma, B cell leukemias, etc.); in the absence of malignancy, they are referred to as monoclonal gammopathies of unknown significance (MGUS). Up to 1% per year of patients with MGUS will develop a hematologic neoplasm.

Clinical features and treatment of paraproteinemic polyneuropathies vary depending on the type of monoclonal gammopathy. The different syndromes associated with monoclonal gammopathies are described in detail in the article on Neuropathies associated with monoclonal gammopathies. Their treatment depends on the underlying clinical syndrome, but, in general, demyelinating polyneuropathies associated with IgG and IgA gammopathies are managed similarly to CIDP. However, treatment of monoclonal IgM-associated polyneuropathies is different and usually requires a more aggressive approach.

Myasthenia gravis. Myasthenia gravis is an immune-mediated disorder characterized by fatigable weakness of the skeletal muscles. Up to 60% of patients initially present with ptosis or diplopia (62) although weakness may involve any combination of extraocular, bulbar, limb, respiratory, and axial muscles. Patients are sub-grouped based on autoimmune and antibody disease mechanisms, target molecules of skeletal muscle, thymic status, genetic characteristics, response to therapy, and disease phenotype. The disorder may be life-threatening, and severe symptoms may require a temporary feeding tube or mechanical ventilation. Several factors can worsen the weakness, including infections, drugs, concomitant medical conditions, or psychological stress. These factors must be considered to select the most appropriate treatment and dosage for patients with myasthenia gravis (see the myasthenia gravis article).

The immunopathogenesis of myasthenia gravis is one of the best understood among the autoimmune diseases. In 85% of the patients, antibodies against the acetylcholine receptor are detected (myasthenia gravis with anti-acetylcholine receptor antibodies or AChR+ myasthenia gravis). These antibodies are mainly IgG1 or IgG3 and can block and decrease the number of AChR receptors by cross-linking and internalization. They also produce complement-mediated lysis of the receptors. Antibodies against the muscle-specific kinase (MuSK) are detected in approximately half of the remaining 15% of the patients (myasthenia gravis associated to anti-muscle specific kinase antibodies or MuSK+ myasthenia gravis). The role that MuSK antibodies may have in the pathogenesis of the disease remains poorly understood as these antibodies are of the IgG4 subclass, with poor ability to activate complement and inability to mediate cross-linking receptor degradation. A third autoantigen, lipoprotein receptor-related protein 4 (LRP4), has been identified in myasthenia gravis. It is present in 18% of double anti-AChR-MuSK-negative patients. Clinical features associated with this antigenic reactivity have been described (164). Its clinical utility remains to be precisely established, as it also is present in some with seropositive myasthenia gravis and controls. Although the remaining patients are referred to as seronegative-myasthenia gravis, the underlying neuromuscular defect is still thought to be antibody-mediated, and response to immunotherapy is similar to seropositive patients.

Inflammatory myopathies. The evolving classification of inflammatory myopathies includes dermatomyositis, polymyositis, inclusion body myositis, overlap myositis, anti-synthetase myositis, and necrotizing myopathy. This heterogeneous group of myopathies presents with muscle weakness and inflammation on muscle biopsy. Dermatomyositis is characterized by proximal muscle weakness associated with typical skin changes. Anti-synthetase myositis presents more acutely than dermatomyositis and is often associated with interstitial lung disease, Raynaud syndrome, arthritis, and “mechanic hands.” Polymyositis commonly presents with subacute proximal weakness. Inclusion body myositis characteristically presents with gradual weakness of the quadriceps, finger flexors, and tibialis anterior muscles and eventually evolves into generalized weakness. Overlap myositis is associated with connective tissue diseases, such as lupus or Sjogren syndrome. Necrotizing myopathy is characterized by acute severe weakness involving proximal muscles of the limbs and, frequently, bulbar and respiratory muscles. The etiology of the inflammatory myopathies is unknown, and the underlying pathophysiology has only been partially identified. Muscle pathology in dermatomyositis is distinct when perifascicular atrophy is present. Polymyositis and inclusion-body myositis show muscle fibers invaded by mononuclear cells. Inclusion-body myositis muscle samples may also show rimmed vacuoles, cytochrome c oxidase (COX)-negative fibers, and filamentous inclusions on electron microscopy. Muscle pathology in necrotizing myopathies is characterized by the presence of abundant necrotic fibers, deposits of the C5b9 membrane attack complex on muscle fiber surface, and the total absence of inflammatory infiltrates. Occasionally, mild inflammatory infiltrates are observed. The inflammatory cells invading nonnecrotic muscle fibers are CD8+T cells, and most of the muscle fibers express major histocompatibility class I. In contrast, dermatomyositis has a higher percentage of B cells and CD4+T cells in the infiltrates. This may suggest that dermatomyositis is primarily due to a humoral-mediated immune response whereas polymyositis and inclusion-body myositis may be due to a cytotoxic T cell-mediated immune response (51).

General aspects of immunotherapy

Before initiation of immunomodulatory or immunosuppressive therapies, several factors must be taken into account. The diagnosis should be well established, the risk-to-benefit ratio of the medications should be considered, and the treating neurologist must be familiar with the potential adverse effects. Patient comorbidities and concomitant treatments influence medication selection. Periodic monitoring of liver and kidney function is recommended for patients taking most immunosuppressants. In women, pregnancy planning is critical as many immunosuppressants are teratogenic. The lack of response to one drug does not mean the patient will not respond to others, and sequential trials with different drugs may be necessary until the appropriate one is found. Time-to-response may be long for some of the drugs, and the treating doctor and patient should be aware of this. Drugs should be given sufficient time to develop their effects and not be withdrawn after a short period of time with the patient considered “resistant” to the drug. It should also be considered (and the patients informed) that in addition to specific short-term side effects, long-term immunosuppression can increase the risk for development of infections and neoplasms.

Commonly used therapeutics

Immune-modulating therapies

Intravenous immunoglobulin. Intravenous immunoglobulin is often an effective treatment most commonly given intravenously in 2 g/kg doses divided over 2 to 5 days. Similar outcomes have been observed with 5% or 10% intravenous infusions and subcutaneous administration (50). The main disadvantages of intravenous immunoglobulin are the need for repeated infusions in many patients, cost (both in time and money), and scarcity in some countries. Intravenous immunoglobulin is relatively safe. The main side effects are usually headache, fever, or hypertension. Serious adverse events such as aseptic meningitis or thrombotic events are rare. For more information, see Intravenous immunoglobulin article.

Subcutaneous immunoglobulin. The availability of subcutaneous immunoglobulins (SQIg) has raised the possibility of self-administered treatment for patients at home, reducing the need for hospital admissions or outpatient infusion clinic visits, as well as the overall cost of immunoglobulin therapy, without loss of effectiveness (69; 28). SQIg is available in 10% to 20% concentrations in the United States. The exact dosing for neuromuscular diseases still needs to be established, though most studies investigating its efficacy used equivalent dosing to IVIG. Bioavailability studies investigating SQIg in patients with primary immune deficiency found that 1.53 times the dose of IVIG was required to establish equivalent serum immunoglobulin levels. The desired monthly dose is divided and administered on a weekly basis to maintain steady-state serum concentrations. This may again be further divided through the week if the patient’s weight technically limits the amount that can be administered at one time.

In most studies, patients tend to have a higher level of satisfaction due to ease of access, convenience, comfort, safety, and medical assistance (87). The most common side effect is an injection site reaction, which is typically mild. Because high immunoglobulin serum concentrations cannot be achieved quickly through subcutaneous administration, it is not recommended as acute treatment for life-threatening symptoms.

Facilitated subcutaneous immunoglobulin (fSQIG) is a newer formulation of SCIg consisting of human immune globulin 10% with recombinant human hyaluronidase, which allows it to be dosed at a similar frequency as intravenous immunoglobulin (75). The addition of hyaluronidase increases absorption and distribution of SQIg by cleaving hyaluronan, which is the main component of the subcutaneous tissue that causes resistance of fluid flow. fSQIg is currently FDA approved for primary immunodeficiency and was shown to be beneficial in multifocal motor neuropathy (159).

Plasma exchange. Plasma exchange is a treatment option for patients with select immune-mediated neurologic disorders who do not respond to other therapies or when a rapid response is needed (120). Among its main disadvantages are that it is costly, time-consuming, and requires central venous access and hospital administration. Plasma exchange is usually well-tolerated, but side effects, such as hypotension, are frequent. It is contraindicated in patients with cardiac disease, sepsis, or coagulopathies and usually requires the use of other immunosuppressants to maintain its effects in the long term.

Immunosuppressants

Steroids. Immune-mediated neuromuscular diseases may be treated with daily or alternate-day dosing of corticosteroids, a regimen suggested to reduce long-term side effects. The most commonly used regimen is prednisone or prednisolone 1 to 1.5 mg/kg for 1 to 3 months followed by a slow taper over a period of months or years (58). Steroids are effective, inexpensive, and widely available. Their main disadvantages are the side effects, which are frequent and diverse. However, when properly used, steroids are usually well-tolerated in most patients.

Steroid-sparing immunosuppressants. Steroid-sparing immunosuppressants are used in the following situations: (1) when there is failure to improve with first-line drugs, (2) when there is insufficient improvement, (3) when steroid dose higher than 40 mg every other day is required to avoid deterioration, (4) when side effects are severe, and (5) when corticosteroids are contraindicated.

Azathioprine. Azathioprine is safe and inexpensive and has been used successfully in several autoimmune disorders. It is a purine analog that inhibits purine synthesis. An important practice point is to first evaluate for thiopurine S-methyltransferase (TPMT) activity prior to initiation of azathioprine in all patients to assess potential risk of side effects and determine the appropriate dose for each patient. Intermediate TPMT activity is a risk factor for increased myelosuppression, and low to absent TPMT is a risk factor for severe, life-threatening myelotoxicity. In some diseases, activity onset is delayed by several months, which may be a consideration in patients with significant symptoms who require a faster therapeutic response (112).

Mycophenolate mofetil. Mycophenolate inhibits inosine monophosphate dehydrogenase, preventing T and B lymphocyte proliferation. It is usually well tolerated, so it is also used when other drugs produce unacceptable side effects. Mycophenolate must be initiated in increasing doses up to 3 gm daily divided in two doses. The main side effects are hyperglycemia, hypercholesterolemia, gastrointestinal symptoms, and electrolyte disorders. For more information, see the Mycophenolate article.

Methotrexate. Methotrexate is a selective irreversible inhibitor of dihydrofolate reductase inhibitor causing decreased purine and thymidylic acid synthesis, which disrupts DNA synthesis and repair. Several doses and regimens have been used, but the most common is 15 mg/week, either oral or subcutaneous, administered in once-weekly doses. When using methotrexate chronically, folic acid supplement (5 mg daily, by mouth) is recommended.

Tacrolimus. Tacrolimus (or FK506) is a macrolide immunosuppressant. It is also a calcineurin inhibitor and inhibits IL2 transcription and T-cell signaling. Tacrolimus was developed to prevent transplantation rejection but is now widely used in many autoimmune diseases. Its side effect profile is similar to cyclosporine, and blood levels should be monitored to avoid toxicity.

Cyclosporine A. Cyclosporine A has been used widely in several autoimmune disorders and in organ transplantation. It is a calcineurin inhibitor that acts mainly to suppress T cell function. It must be started slowly, and blood levels should be monitored to avoid toxicity. The main side effects are hypertension, gingival hyperplasia, skin rash, tremor, and nephrotoxicity.

Cyclophosphamide. Cyclophosphamide is an alkylating agent used as a chemotherapeutic agent in hematologic neoplasms. It produces DNA toxicity and subsequent cell death. It can be used either orally or intravenously at doses that vary depending on the disease and the route of administration. Cyclophosphamide has been reported to be beneficial in patients with a variety of autoimmune diseases resistant to other drugs. It is a powerful immunosuppressant, though its severe side-effect profile limits its use to drug-resistant patients. The main side effects range from alopecia to sterility. The most severe side effects include hemorrhagic cystitis, bone marrow aplasia, hematologic malignancies, and interstitial pulmonary fibrosis.

Biological agents. Several new agents have emerged as treatments for immune-mediated neuromuscular diseases. Most are specific therapies discovered and used in other diseases that influence cells or pathways presumably involved in the pathogenesis of the autoimmune neuromuscular disorders. These agents are monoclonal antibodies (eg, rituximab and alemtuzumab) or recombinant proteins (eg, interferon and etanercept). One disadvantage of the biological agents is the development of autoantibodies against the agents, which cause them to lose their effect.

Rituximab. Rituximab is a chimeric (mouse/human) monoclonal antibody against the B cell marker CD20. This marker is present only in cells of B lineage apart from early B-cell precursors and plasma cells. A typical dose of rituximab is 375 mg/m2 weekly for 4 weeks with additional courses administered every 6 months as needed. However, dosing regimens may vary depending on the disease being treated. The B cell depletion can last for longer than 6 months.

Rituximab’s most frequent side effects are related to infusion reactions, which are usually mild. However, there have been reported cases of progressive multifocal leukoencephalopathy in patients treated with rituximab for hematologic malignancies, rheumatoid arthritis, and myasthenia gravis (02). In rheumatoid arthritis, the estimated incidence is about 1 in 25,000 patients, but it is frequently fatal (33). Other severe side effects are pulmonary toxicity, anaphylactic reactions, and cell lysis syndrome.

Eculizumab. Eculizumab is a humanized monoclonal antibody with high affinity targeting of the human terminal complement protein C5. This prevents cleavage of C5 into C5a and C5b, respectively preventing chemotaxis of proinflammatory cells and formation of membrane attack complexes. As patients on eculizumab are at a higher risk of meningococcal infections, the Advisory Committee on Immunization Practices recommends immunizing with the meningococcal vaccine at least 2 weeks prior to administering the first dose. Some common side effects include headache, upper respiratory infections, and nausea.

Ravulizumab. Ravulizumab is a modified version of eculizumab that is longer acting and designed to maintain therapeutic serum concentrations over 8 weeks. Like eculizumab, it is a humanized monoclonal antibody targeting complement protein C5 and carries the same immunization recommendations (158).

Efgartigimod. Efgartigimod is a novel neonatal Fc receptor (FcRn) antagonist. The neonatal FC receptor prolongs the lifespan of endogenous IgG by protecting it from lysosomal degradation and recycles it back into circulation (38; 38). By binding to the neonatal Fc receptor, efgartigimod promotes IgG and pathologic antibody degradation. Some possible side effects include upper respiratory infections and urinary tract infections (78).

The following drugs have been used in small series or single cases. In some patients, a beneficial effect is reported, but worsening or severe side effects are also found. These drugs may be promising treatments but should be used with caution as further research is needed.

Alemtuzumab. Alemtuzumab is a humanized monoclonal antibody against the CD52 antigen, present in mature lymphocytes. Alemtuzumab is very potent in depleting lymphocytes, so it results in a severe lymphopenia that increases the risk of opportunistic infections. Moreover, some data suggest that patients may be at risk to develop other autoimmune disorders, particularly some B-cell mediated diseases, such as thyroid autoimmune disease or thrombotic thrombocytopenic purpura.

Interferons. Interferon alpha and beta are natural cytokines belonging to the type I interferon group. Recombinant alpha interferon was developed for hepatitis C treatment whereas recombinant beta interferons are used for first-line treatment of multiple sclerosis. Both have been used in neuromuscular diseases with anecdotal improvement in a few patients. Their main side effects include fever, chills, headache, and allergic reactions.

Etanercept. Etanercept is a synthetic protein consisting of a TNF receptor and an immunoglobulin Fc fragment linked together. Etanercept acts as a decoy receptor, binding soluble TNF and, thus, reducing TNF levels. TNF inhibitors have been used for inflammatory neuropathies and myopathies, but they have also been described to induce demyelinating neuropathies. Their main side effects are respiratory infections, injection-site reactions, and headache. Tuberculosis screening must be performed prior to treatment.

Upcoming treatments. Immunotherapy for neuromuscular diseases is a very active field of research, and multiple clinical trials are currently underway for a number of medications.

Medication	Mechanism of action	Frequency of dosing	Diseases being studied
Zilucoplan	Complement C5 inhibitor	Daily subcutaneous dosing	Myasthenia gravis
Batoclimab	FcRn antagonist	Weekly subcutaneous dosing	Myasthenia gravis
Rozanolixizumab	FcRn antagonist	Weekly subcutaneous dosing for 6 weeks	Myasthenia gravis

Treatment of autoimmune neuromuscular conditions

We now review and summarize the evidence available for the use of the different medications according to specific disorders and describe current and emerging treatments.

Chronic inflammatory demyelinating polyneuropathy

Intravenous immunoglobulin. Intravenous immunoglobulin is one of the first-line treatments for CIDP and has been found to be of benefit in about two thirds of patients (135). A subsequent study in 49 patients with CIDP found that the long-term benefits persisted over a median observation time of 45 months (147). Improvement occurs after several weeks of treatment and lasts from 2 to 48 weeks (57). The ICE study, a randomized, placebo-controlled trial, showed that 54% of patients responded to 10% intravenous immunoglobulin whereas only 21% in the placebo group had a response. The probability of relapse was 13% in the treated patients compared to 45% in the placebo group, confirming that treatment effect persists beyond the relapse phase (80). In an expert opinion article regarding treatment, a loading dose of 2 g/kg followed by 1 g/kg every 3 weeks is recommended for most cases, although a higher maintenance dose of 2 gm/kg every 3 weeks may be necessary for patients with more severe disease (05). Repeated courses are often needed, with the frequency of the courses depending on when symptoms reappear or worsen again. However, if no improvement occurs within 6 months, then further treatment with IVIG should be aborted. Before escalating therapy and considering the disease refractory, it is important to revisit the diagnosis as misdiagnosis is frequent (85; 05). Some patients who do not respond to IVIG may respond well to either steroids or plasma exchange (92). Comparative studies against steroids or plasma exchange showed no differences with intravenous immunoglobulin in disability reduction (57).

Subcutaneous immunoglobulin. Subcutaneous immunoglobulin (SC-Ig) has emerged as an alternative to intravenous administration of immunoglobulin. A meta-analysis of four trials involving 90 patients showed that SC-Ig had comparable efficacy to IVIG in preventing muscle strength deterioration. The side effect profile was milder, with up to 3.3% of patients experiencing moderate to severe side effects compared to 20% to 50% of patients receiving IVIG. Most patients did have mild injection site reactions, such as redness and swelling (134). In a study comparing SC-Ig and IVIG in treatment naïve patients, the efficacy was similar in both treatments, though SC-Ig took longer to reach maximal improvement (103). With respect to dosing, a randomized, double blinded, placebo-controlled study (the PATH trial) showed that both low-dose (0.2 g/kg/week) and high-dose (0.4 g/kg/week) SC-Ig were superior to placebo in patients who were IVIG-dependent. Patients on the higher dose tended to have fewer relapses though it was not statistically significant when compared with the lower dose. When comparing to previous IVIG studies, the number needed to treat to prevent relapse in patients taking the SQIg was similar (154). Quality of life measures are also maintained or improved with SC-Ig treatment (70).

Steroids. Corticosteroids are another first-line therapy widely used for CIDP treatment. One randomized, unblinded trial showed effectiveness of prednisone 120 mg every other day at 12 weeks, with significant improvement in physical exam, touch-pressure sensitivity of the hands, hand grip, and nerve conduction studies (54). Many randomized as well as uncontrolled trials and case series suggest that steroids are effective in CIDP treatment (Joint Task Force of the EFNS and the PNS 2010a; Joint Task Force of the EFNS and the PNS 2010b). A randomized trial has suggested similar effectiveness and lower side effects when using pulsed monthly dexamethasone compared to standard steroid regimens (155). This response is sustained in a significant proportion of patients, with some evolving to remission as has been seen with IVIG (56). Another clinical trial showed that IVIG was associated with slightly better outcomes than intravenous methylprednisolone (122). Interestingly, the patients on methylprednisolone were found to have much longer remission times than the IVIG group, suggesting that for a subset of patients, intravenous methylprednisolone may be useful even for long-term treatment (123). As per the expert opinion article for dosing of oral prednisone, it is recommended to start at 60 mg per day for 4 to 8 weeks followed by a slow taper (05). Monthly regimens may be given with either IV methylprednisolone 500 mg per day for 4 days or oral dexamethasone 40 mg per day for 4 days. Some patients need shorter intervals between treatments. As noted with IVIG, it is recommended to discontinue therapy, reconsider the diagnosis, and possibly escalate treatment if no improvement occurs within 6 months.

A subset of patients with CIDP, particularly those with pure motor forms of CIDP, may worsen with steroids. This must be considered in patients who deteriorate while on steroid treatment (107).

Plasma exchange. A Cochrane review of two randomized controlled trials of plasma exchange compared with sham exchange showed a significant improvement in symptoms (05). Treatment is typically given every other day for a total of five sessions. However, some observational studies suggest that patients who are not also on steroids or other immunosuppressants can have a rapid and severe relapse 1 to 2 weeks after discontinuing plasma exchange (108).

Azathioprine. One small trial comparing azathioprine with placebo as a steroid-sparing agent showed no benefits (53). Several case series describe patients responding to azathioprine (99). A randomized trial has been proposed to determine its role in treating patients with CIDP.

Cyclosporine A. Several case series have reported clinical improvement with cyclosporine A in patients with CIDP (99). Improvement was reported in 30 of 41 patients. Although this may support the use of cyclosporine as add-on therapy with low levels of evidence, the case series were heterogeneous, and no randomized trials are available. The main side effects of cyclosporine are hypertension, gingival hyperplasia, skin rash, tremor, and nephrotoxicity. Blood cyclosporine levels and renal function should be monitored to decrease side-effect rates.

Methotrexate. A trial with methotrexate was published in 2009 and compared the effectiveness of methotrexate with placebo. Primary outcome was number of responders versus nonresponders, which was based on the ability to decrease intravenous immunoglobulin or steroid doses more than 20%. The trial did not demonstrate any differences between methotrexate and placebo. These results preclude the generalized use of methotrexate in patients with CIDP (140). However, in select patients who have remained refractory to other treatments, it may be beneficial (48).

Mycophenolate mofetil. In small case series that included a total of 29 patients, 11 responded to mycophenolate treatment. There have been no controlled trials. As with methotrexate, mycophenolate may be a safe alternative for patients with a poor response to conventional therapies, although there are insufficient data to support widespread use in patients with CIDP (99).

Rituximab. A Cochrane review identified a total of 33 patients with CIDP who were treated with rituximab (99). Those with co-existent hematologic disease (19 of 33 patients) had a more favorable response (97). One case series showed a beneficial response in 9 of 13 patients, of which six were previous nonresponders (15). A subsequent study demonstrated improvement in 10 of 11 patients who were refractory to IVIG and glucocorticoids (114). Although the lack of controlled trials and the adverse events profile preclude the generalized use of rituximab in CIDP, in select cases, especially when CIDP co-occurs with hematologic diseases, it may be considered as an earlier option.

Autoimmune nodopathies

Steroids. Corticosteroids are part of the standard treatment as evidence shows they improve symptoms in most patients (132; 111; 47; 36). However, the improvement tends to be transient and incomplete, so other steroid-sparing agents should be initiated concomitantly (67).

Rituximab. Rituximab has emerged as a treatment of choice in IgG4-mediated neurologic diseases (37). In autoimmune nodopathies, multiple small studies suggest that the majority of patients improve with rituximab (111; 26; 77; 67). There is also evidence that earlier initiation of rituximab leads to improved outcomes (133). After the initial induction of rituximab, further treatment can be decided based on clinical status, antibody titers, serum neurofilament, and anti-CD19+ or CD27+ B-cell levels (67).

Other therapies. Other steroid-sparing agents, including azathioprine, cyclophosphamide, methotrexate, tacrolimus, and mycophenolate mofetil have yielded inconsistent results in case reports but are potential options (111; 46; 67). Plasma exchange may be beneficial in an acute setting or may be used as a bridging therapy (67). IVIG is typically ineffective in these patients (132; 111; 47).

Multifocal motor neuropathy

Intravenous immunoglobulin. Intravenous immunoglobulin is the accepted treatment for multifocal motor neuropathy and the only one that has been included in the practice guidelines as being clearly effective (Joint Task Force of the EFNS and the PNS 2010c). Despite treatment, however, progression to axon loss occurs in some cases over time and is associated with increased disability. A meta-analysis of several trials reports that up to 80% of patients with multifocal motor neuropathy have improved strength; however, only 40% show improved disability status (55). In one study, up to 94% of patients benefited from intravenous immunoglobulin treatment (29). The only significant differences between responders and nonresponders were disease duration and axonal loss in electrophysiologic studies. The most recent Cochrane review reported that intravenous immunoglobulin is beneficial in improving strength and disability in patients with multifocal motor neuropathy, but withdrawal of therapy may result in clinical worsening of disease (88).

Subcutaneous immunoglobulin. Over the past few years, multiple studies have shown comparable efficacy of subcutaneous immunoglobulin with intravenous immunoglobulin. A meta-analysis of 50 patients with multifocal motor neuropathy demonstrated comparable efficacy between IVIG and SCIg in preventing muscle strength deterioration with fewer side effects (134). In a prospective trial involving 18 patients who had been stable on IVIG, transition to fSCIg at the equivalent dose and frequency of their IVIG resulted in less systemic side effects and no significant difference in muscle strength and disability (75).

Other treatments. Although intravenous immunoglobulin is the mainstay for treatment of multifocal motor neuropathy, the use of steroids, cyclophosphamide, and rituximab have been evaluated for patients trying to reduce intravenous immunoglobulin dose and frequency and for those who are refractory to IVIG.

Steroids. Steroids are not recommended in the treatment of multifocal motor neuropathy because of their proven ineffectiveness in most patients. Furthermore, some patients may worsen with steroids (Joint Task Force of the EFNS and the PNS 2010c). The reason for this is not well understood.

Rituximab. There is conflicting evidence for the use of rituximab in multifocal motor neuropathy (95; 142). A pilot study concluded that rituximab can be safely given to patients with multifocal motor neuropathy but was unable to reduce the amount of intravenous immunoglobulin required (31). Also, some cases of clinical worsening have been reported (141).

Evidence-based guidelines regarding multifocal motor neuropathy diagnosis and management have been published in two extensive reviews (151; Joint Task Force of the EFNS and the PNS 2010c; 55).

Paraproteinemic neuropathies

Treatment of IgG and IgA paraproteinemic neuropathies. Few studies specifically address the treatment of IgG and IgA paraproteinemic neuropathies. Only one randomized trial assessing plasma exchange effectiveness in these neuropathies was included in a Cochrane Review (52). The review found that plasma exchange may be effective for short-term therapy in these patients. In the same review, other case series were analyzed (04). In general, treatments used for IgG and IgA polyneuropathies are those usually employed in CIDP (prednisone, intravenous immunoglobulin, cyclophosphamide, etc.), and results are like the ones obtained in CIDP. Nobile-Orazio found that 81% of 67 patients with IgG or IgA monoclonal gammopathy of unknown significance (MGUS) and a demyelinating neuropathy responded either to intravenous immunoglobulin, steroids, or plasma exchange (121). Another retrospective study found intravenous immunoglobulin to be beneficial in 8 of 20 patients with IgG MGUS (65). Other smaller series point to similar results in IgG or IgA MGUS associated to demyelinating neuropathies (04). Generally, a hematology referral may be considered to exclude malignancy, and treatment regimens similar to CIDP may be used.

Treatment of IgM paraproteinemic polyneuropathy (MGUS PN). Several treatments have been tested in IgM paraproteinemic polyneuropathy. The general feeling is that response to immunotherapy is worse than in CIDP or other demyelinating neuropathies, but some treatments have proven to be effective. Management is based on both M-protein levels and on the patient’s overall clinical picture. Close collaboration with a hematologist is also recommended. Periodic measurements of immunoglobulin quantitation and serum immunofixation may be done every 6 to 12 months, and treatment can be considered if the monoclonal protein rises above 1.5 g/dL (139). A summary of the available evidence is described:

Intravenous immunoglobulin. Two trials have been reported regarding intravenous immunoglobulin effectiveness in IgM paraproteinemic neuropathy. One of them included 22 patients and provided evidence of intravenous immunoglobulin effectiveness in the short term for monoclonal IgM-associated neuropathies compared to placebo (34). The second trial was a clinical description of 11 patients, of whom four of five were reported to respond to different immunomodulatory therapies (40). A study of 14 patients did not find any benefit of IVIG in patients with anti-MAG neuropathy (148). The study by Comi and colleagues determined a favorable opinion by Cochrane reviewers regarding the use of intravenous immunoglobulin in IgM MGUS (98).

Plasma exchange. Plasma exchange had been reported to be temporarily effective in some cases. However, two controlled studies did not demonstrate effectiveness of plasma exchange. One of them compared plasma exchange with placebo in 44 patients already taking chlorambucil, 39 of which were anti-MAG positive. No differences were detected (126). The other study compared therapeutic plasma exchange with sham plasma exchange in 39 patients in all classes of MGUS. Patients with IgG or IgA did respond, but the 21 with IgM MGUS did not (52).

Steroids. A review of case reports and open series described that about half of patients with IgM MGUS PN responded to steroid therapy when associated to other treatments but not when used in monotherapy. No controlled trials are available, and, in general, steroids are not usually used as a first-line therapy in these cases (121).

Interferon alpha. One open-label trial suggested interferon alpha effectiveness in 8 of 10 treated patients with demyelinating polyneuropathy associated with anti-MAG antibodies (102). A controlled trial failed to confirm these preliminary data and did not detect differences between interferon alpha and placebo-treated patients (101). Thus, interferon alpha cannot be recommended.

Rituximab. In a randomized, placebo-controlled trial in 26 patients with IgM monoclonal gammopathy and anti-MAG antibodies, 4 of 13 patients treated with rituximab showed improvement in INCAT disability score whereas none in the placebo group showed improvement. The rituximab group also performed better in the 10-minute walk test. Improvement was evident in those patients with higher anti-MAG titers and worse sensory symptoms (41). In an open-label trial by Pestronk and colleagues, 80% of 21 patients with IgM MGUS PN treated with rituximab improved their strength compared with untreated patients. Average improvement in strength was 13% in the first year and 23% in the second, but no data on ataxia and sensory symptoms were available (129). An open trial with 17 patients also showed benefit in up to nine patients treated with rituximab (119). In a case series of anti-MAG patients, high-dose rituximab resulted in a beneficial response in four of eight patients. The same authors showed similar results in a previous open trial with standard rituximab doses (137; 136). Another case-series reported benefit in 62% of 13 patients when treated with rituximab (16). Of those, only two patients had significant improvement (more than 10 points in that same score).

A case-series report suggested that adding fludarabine to rituximab can improve clinical outcomes without additional significant side effects (66).

An unpublished controlled trial by Leger and colleagues that was presented at the meeting of the Peripheral Nerve Society failed to show effectiveness in the main outcomes in anti-MAG patients treated with rituximab when compared to those treated with placebo in patients with polyneuropathy with anti-MAG antibodies. However, improvement in secondary outcome measures suggests that rituximab may still have a role in the treatment of anti-MAG neuropathy (94).

A retrospective study by Campagnolo and associates of 33 patients with anti-MAG neuropathies, 25 of which had MGUS and five had Waldenstrom macroglobulinemia, demonstrated that rituximab had similar efficacy between the two groups (56% and 44%, respectively). In addition, they found that six patients who did not respond after the first treatment improved after a second rituximab cycle was given with recurrence of symptoms (27).

There are growing data to support the use of rituximab in monoclonal IgM-associated neuropathies in select patients (14; 45). However, the side effect profile of rituximab limits more widespread use.

Other therapies. Chlorambucil had some benefit in up to one third of IgM MGUSP patients when used in monotherapy. It was also found to be beneficial when treated with obinutuzumab, an anti-CD20 antibody, in two patients with anti-MAG antibody polyneuropathy (22).

Cyclophosphamide has failed to show effectiveness in IgM MGUSP patients when used in monotherapy, but it may be effective when added to steroids or plasma exchange.

There are case reports describing effectiveness of chemotherapeutic agents (eg, fludarabine, cladribine), but they should not be used unless and until larger trials demonstrate their effectiveness (98).

Myasthenia gravis. The pathophysiology of the two major types of myasthenia gravis, anti-AChR and anti-MuSK, affect approach to treatment. Unlike anti-AChR myasthenia gravis, which is predominantly IgG1- and IgG3-mediated, anti-MuSK is predominantly IgG4-mediated. Many new and emerging treatments for myasthenia gravis target the complement cascade and would be ineffective in anti-MuSK patients.

Corticosteroids. After more than 70 years of treating myasthenia gravis with corticosteroids, there are no randomized clinical trials supporting their usefulness (145). However, the results of many observational studies support their efficacy, and it would be unethical to undertake placebo-controlled trials at this time. Of note, although patients may have paradoxical worsening of symptoms with initiation of prednisone, the effects may be mitigated with coadministration of IVIG (49).

Azathioprine. In myasthenia gravis, two randomized double-blind trials compared azathioprine plus steroids versus steroids alone; the results support the use of azathioprine in myasthenia gravis as a steroid-sparing agent (116; 23). Moreover, it can also be useful as a first-option drug in elderly patients, as demonstrated in several case reports.

Mycophenolate mofetil. Mycophenolate mofetil is commonly used as a steroid-sparing option. A retrospective study of 102 patients showed benefit in AChR+ patients after 6 months as monotherapy (72). A beneficial response in drug-resistant patients with myasthenia gravis has been reported in case series and open-labeled studies (68). However, two randomized controlled trials comparing mycophenolate plus prednisone versus prednisone alone did not show differences in muscle strength or dose of prednisone between groups (115; 143). It is important to note that tapering mycophenolate mofetil can rapidly cause a relapse in symptoms that is responsive to increasing the dose. If tapering is desired, reducing the dose by 500 mg/day every 12 months is recommended (76).

Cyclosporine. Two randomized studies endorsed the use of cyclosporine in myasthenia gravis (150; 149). Treatment is usually initiated when patients do not respond to steroids or azathioprine, if azathioprine cannot be used, or when a rapid therapeutic response is needed, and steroids have not been efficacious.

Tacrolimus. Tacrolimus has been used as a second-line drug in patients with refractory myasthenia gravis. Data supporting its use are controversial. A single randomized, unblinded study performed in recently diagnosed and untreated patients with myasthenia gravis compared prednisone plus tacrolimus versus prednisone alone. The authors reported a shorter time to reach minimal manifestation status and lower doses of prednisone in the tacrolimus group (117). Several case series have been published supporting the use of tacrolimus as a steroid-sparing agent (48). One study comparing 15 patients with refractory myasthenia gravis taking tacrolimus and prednisone with 30 patients taking either prednisone alone or with azathioprine found that both groups had clinical improvement on MGFA-QMG and ADL-MG scores, although reduced circulation of CD4+CD25+ cells was seen only in the tacrolimus group (09). In contrast, a randomized, double-blind, placebo-controlled trial demonstrated no effect of tacrolimus as a steroid-sparing agent in a cohort of 80 myasthenia gravis patients, though secondary analysis did show some steroid-sparing effect (161). Another randomized, double-blind, placebo-controlled trial in glucocorticoid-resistant patients also did not demonstrate any difference in change in QMG score at 24 weeks. However, post-hoc analysis did demonstrate a statistically significant difference for QMG score reduction of at least four points in the tacrolimus group (162).

Methotrexate. The use of methotrexate in patients with myasthenia gravis was anecdotal until 2011, when Heckmann and coworkers published the results of a single-blind trial comparing methotrexate and azathioprine as steroid-sparing agents in 24 patients (71). Steroid dose reduction was possible in both groups, and no significant differences were observed. The utility of methotrexate is now in question after a study by Pasnoor and colleagues (127). Their randomized double-blinded placebo-controlled trial of 50 patients evaluating the steroid sparing benefit of methotrexate over 1 year failed to show any benefit. However, the trial may have been under-powered and too short in duration, and most of the patients were already taking a lower dose of prednisone (127). As noted in the most recent 2020 consensus guidelines for the management of myasthenia gravis, oral methotrexate may still be considered a treatment option in patients who have failed or were unable to tolerate other steroid sparing agents (118).

Cyclophosphamide. Cyclophosphamide was used in the past in patients with severe symptoms and poor response to other drugs. In fact, a randomized trial comparing cyclophosphamide plus steroids versus steroids alone demonstrated a higher improvement of myasthenic symptoms and lower doses of steroids in the cyclophosphamide group (44). A study demonstrated clinical improvement in six of eight patients with refractory myasthenia gravis who were treated with monthly doses of cyclophosphamide (30 to 50 mg/kg/month) for 6 months, although clinical worsening was seen after discontinuation of the medication (64). Due to the risk of severe side effects, however, cyclophosphamide is not commonly used and is reserved as a rescue drug for resistant patients.

Rituximab. Rituximab is increasingly being used for the treatment of myasthenia gravis. A review of 47 publications containing 169 patients with myasthenia gravis showed it to be an effective and well-tolerated treatment for both anti-AChR+ and anti-MuSK+ patients.

Anti-MuSK+ myasthenia gravis. Studies show that it is significantly more effective in patients with anti-MuSK antibodies (146; 30; 144). In a prospective trial of treatment-refractory myasthenia gravis, four of nine MuSK+MG patients were able to discontinue all other immunotherapy when treated with rituximab compared to 1 in 10 AChR patients (12). A multicenter, prospective study compared MuSK+ patients treated with rituximab with those who were treated with non-rituximab medications (73). The primary clinical endpoint was minimal manifestation and pharmacological remission in addition to either low-dose dual oral therapy or prednisone monotherapy. At the end of the study, 58% of patients on rituximab met this endpoint or better compared with 16% of controls. In addition, in the rituximab arm 29% of the patients were on prednisone and 8% on multiple immunotherapies as compared to the control group with 74% on prednisone and 58% on multiple medications. The final mean dose of prednisone in the rituximab group was 4.5 mg daily compared to 13 mg in controls. In addition, a retrospective study evaluated the effect of rituximab dosing on clinical benefit and relapse rate in 25 MuSK+ patients. Those treated with a protocol of 375 mg/m2 weekly for 4 weeks followed by two monthly doses had reduced relapse rates compared to patients in the second group who were treated with 375 mg/m2 weekly for 4 weeks and those in the third group who received 1 g doses 2 weeks apart (35).

Anti-AChR+ myasthenia gravis. One study involving 12 patients with refractory AChR+ MG found that treatment with low dose rituximab (600 mg) given at 0, 6, and 12 months led to improved quantitative myasthenia gravis scores and suppression of CD19+ cells at 18 months (96). In addition, there is evidence suggesting improved outcomes with introduction of rituximab earlier in the course of the disease (21). The RINOMAX trial investigated the efficacy of a single rituximab dose of 500 mg compared to placebo as initial immunosuppressive therapy for newly diagnosed patients, although prednisone doses less than 40 mg, IVIG, and plasma exchange within 12 months of screening were allowed (130). At the end of the study, 71% of patients met the primary endpoint of minimal disease manifestation at 16 weeks (defined as QMG score of less than or equal to four with prednisone dose of 10 mg or less and no need of rescue treatment) in the rituximab group versus 29% in the placebo group.

Eculizumab. Eculizumab is an FDA-approved therapy for treatment-resistant patients with AChR+ generalized myasthenia gravis. The REGAIN trial was a double-blinded, placebo controlled, multicenter study of 125 patients with treatment-resistant myasthenia gravis studied over 26 weeks. Although the study did not reach its primary endpoint of a significant difference in the myasthenia gravis activities of daily living score (MG-ADL), there was a significant improvement in the quantitative myasthenia gravis score (QMG). In the responder analysis for MG-ADL and QMG, more patients achieved a clinically meaningful response with eculizumab. In addition, fewer patients on eculizumab had exacerbations, used rescue medications, or were admitted to the hospital (79). Follow-up analysis of the open-label extension period of REGAIN demonstrated persistence of the beneficial effects of eculizumab for up to 3 years, with over half of patients achieving minimal manifestation status or pharmacological remission (113). As per the 2020 consensus guidelines on management of myasthenia gravis, eculizimab is a potential treatment option in severe, refractory AChR+ patients although it may be cost-prohibitive (118). Because the pathophysiology of anti-MuSK involves IgG4 antibodies that do not activate compliment cascade, eculizumab is not thought to be effective in these patients.

Ravulizumab. Ravulizumab is a modified form of eculizumab allowing administration in 8-week intervals rather than 2-week intervals. It was FDA approved for the treatment of AChR+ patients after a randomized, double-blinded, placebo-controlled trial of 175 patients over 26 weeks demonstrated improvement in both the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) and QMG within 1 week, with maximum improvement between weeks 4 and 10, which was sustained through the full 26 weeks (158).

Efgartigimod. Efgartigimod is an FDA-approved therapy for the treatment of AChR+ patients with myasthenia gravis. The ADAPT trial was a double-blinded, placebo-controlled, multicenter study of 167 patients studied over 26 weeks (78). Efgartigimod was dosed 10 g/kg and given on a weekly basis for 4 weeks. Improvement in symptoms was noted within the first week, with maximum improvement noted between weeks 4 and 5, followed by a gradual worsening of symptoms over the following weeks. Of the MG-ADL responders, 32% had a response that lasted 6 to 7 weeks, 23% lasted 8 to 11 weeks, and 34% lasted more than 12 weeks. Currently, there are no guidelines on how often additional cycles of efgartigimod should be given, though the FDA recommends further cycles be given based on clinical response and no sooner than 50 days from the start of the previous cycle (74).

Intravenous immunoglobulin. The administration of intravenous immunoglobulin is reserved for those patients with clinical exacerbations or crisis who are poorly controlled with other drugs. Intravenous immunoglobulin is also used in patients before thymectomy. Two prospective randomized controlled trials have demonstrated the effectiveness of intravenous immunoglobulin in the treatment of myasthenia gravis exacerbations. Gajdos and colleagues reported similar degrees of improvement in 87 patients randomized to intravenous immunoglobulin or plasma exchange (60). Lower rates of complications were observed in the intravenous immunoglobulin group. In the second study, Zinman and colleagues reported a higher improvement rate in the intravenous immunoglobulin group in 51 patients randomized to intravenous immunoglobulin or placebo (163). Other studies have demonstrated the utility of intravenous immunoglobulin in the perioperative period (128). Although small, open-label studies suggest that intravenous immunoglobulin may be helpful as maintenance therapy (01; 138). One randomized controlled trial showed no difference between IVIG and placebo in chronic, stable disease (160).

Subcutaneous immunoglobulin. Subcutaneous immunoglobulin may be used as an alternative for patients who were being treated with IVIG. An open-label, phase 3 clinical trial investigated its utility in 22 patients with a mild to moderate myasthenia gravis exacerbation, finding similar efficacy to previous trials on IVIG (13). A retrospective cohort of nine patients put on SC-Ig also found clinical stability or improvement of symptoms (20). In both groups, patients reported high satisfaction with treatment. It is of note that SC-Ig was not studied in patients with severe myasthenia gravis exacerbations and is currently not recommended in those patients as initial therapeutic levels may not be adequate for quickly reversing symptoms.

Plasma exchange. Intravenous immunoglobulin has comparable efficacy to plasma exchange in the treatment of patients with moderate to severe myasthenia gravis. Both treatments are well tolerated, and the duration of effect is comparable (11). Plasma exchange may be more effective than IVIG in MuSK+ patients. In the setting of a myasthenic crisis, plasma exchange is preferred to IVIG by expert consensus as it is thought to be more effective and work faster (144).

Inflammatory myopathies

Corticosteroids. Corticosteroids are the first-line drug for inflammatory myopathies although their efficacy has not been tested in randomized controlled trials. The response is normally rapid, and benefits are commonly observed within the first 3 months of treatment. Once the maximum benefit is reached, progressive tapering is recommended. Despite the absence of randomized trials, Oddis and colleagues reviewed different steroid regimens and observed that 81% of patients improved when the drug was started at 1 mg/kg per day for 4 to 6 weeks (124). Treatment may be given over years; however, in most patients an additional immunosuppressive agent will be necessary (106). A 3- to 5-day course of 1g intravenous methylprednisolone may be given to patients who present with severe symptoms in addition to other organ involvement (32).

Intravenous immunoglobulin. Intravenous immunoglobulin has been demonstrated to be effective in double-blind, placebo-controlled trials in patients with refractory dermatomyositis (39; 03). Moreover, several open-label studies support the combination of corticosteroids and intravenous immunoglobulin in severely affected dermatomyositis patients, especially in the first months of treatment. In polymyositis, an open-label study showed improvement in 25 of 35 chronic refractory patients and allowed a decrease in the dose of prednisone in all patients (104). Subcutaneous immunoglobulin is also an option in these patients. Gelardi and colleagues reported its efficacy in six patients with severe disease following 6 months of IVIG and as initial therapy in seven patients with moderate disease (61).

Azathioprine. In polymyositis and dermatomyositis, a single double-blind, randomized study comparing azathioprine plus prednisone versus prednisone alone did not find any difference in muscle strength, CK levels, or histological damage after 3 months of follow-up (25; 24). However, the use of azathioprine as a second-line drug in inflammatory myopathy is supported by the results of small case series and case reports.

Cyclosporine. Cyclosporine is commonly used in dermatomyositis and polymyositis patients who do not respond to steroids alone or in combination with azathioprine or methotrexate. A single randomized study compared methotrexate versus cyclosporine in patients with drug-resistant inflammatory myopathy and did not find significant differences in muscle strength or CK levels after 6 months of follow up (156). Moreover, series of cases suggest that cyclosporine can be efficacious in up to 70% of patients treated.

Methotrexate. Methotrexate has been used in inflammatory myopathy for more than 50 years even though its efficacy versus placebo has not been tested in randomized controlled trials. However, several open-label studies have been published supporting the use of methotrexate in inflammatory myopathy. An open-label, nonrandomized study showed that 88% of 25 patients with steroid-resistant polymyositis or dermatomyositis improved significantly, and 43% were able to decrease the dose of steroids (17). No differences in the rate of improvement were found in a double-blind series of cases comparing azathioprine versus methotrexate (110). Moreover, in a randomized cross-over study comparing methotrexate and azathioprine versus methotrexate alone, 12 of 15 patients treated with methotrexate and azathioprine had improved muscle strength compared with only 4 of 15 patients in the group given methotrexate alone (157).

Mycophenolate. Mycophenolate has also been used in refractory polymyositis and dermatomyositis. Few small series of patients have shown a significant improvement in muscle strength and decrease in CK levels (100), but no randomized study has been performed to date.

Tacrolimus. In inflammatory myopathy patients, only preliminary data have been published. In a single open-label study, all polymyositis cases with interstitial lung disease refractory to other drugs showed improvement of muscle strength when they were treated with tacrolimus (125). A retrospective study showed a significantly longer disease-free survival period in 49 patients with PM/DM-related interstitial lung disease compared to conventional treatments (steroids with or without azathioprine or methotrexate) (93).

Cyclophosphamide. The efficacy of cyclophosphamide in inflammatory myopathy is based on case reports and case series. In 1989, a retrospective study showed that only 14% of patients with inflammatory myopathy treated with intravenous bolus dose cyclophosphamide had improved muscle strength, but up to 19% of patients had serious adverse events (18). The treatment is commonly reserved for patients with interstitial lung disease. However, this recommendation is again based on case series as no randomized controlled study has been performed. Improvement in muscle strength and respiratory status has been reported in 26 of 39 patients treated to date (100).

Rituximab. Rituximab has shown efficacy in the treatment of some patients with drug-resistant dermatomyositis or polymyositis. In patients with drug-resistant dermatomyositis, two open-label pilot trials showed improvement in up to 75% of the patients (152). One review of 458 patients with idiopathic inflammatory myopathy showed that 78.3% of patients had some improvement of symptoms. Patients with autoantibodies and shorter disease duration were especially likely to benefit (59). In a retrospective study of 26 patients, the 11 who were antibody positive had significantly major improvement compared to the 15 who were autoantibody negative (10).

Leflunomide. Leflunomide, an immunomodulatory drug that inhibits pyrimidine synthesis, was found to be effective in five patients with drug-resistant inflammatory myopathy (19). The drug is normally used at a dose of 20 mg/day with no important secondary events; however, these anecdotal results must be confirmed in further studies.

TNF-alpha antagonists. TNF-alpha antagonists have been evaluated as treatment for inflammatory myopathies in open-label studies. Some case reports suggest that anti-TNF therapies are effective in drug-resistant inflammatory myopathies whereas other open-label trials showed no benefit (100). A randomized, double-blind, placebo-controlled crossover study of 12 patients investigated whether infliximab was effective in treatment-resistant patients with dermatomyositis and polymyositis, measured by improvement in strength. Six patients received 5 mg/kg of infliximab and the other six received placebo. After 16 weeks, one patient in the infliximab group showed improvement whereas none of the placebo patients had any improvement. Three patients who were on infliximab were then started on a 7.5 mg/kg dose whereas the patients on placebo were started on 5 mg/kg dose. One of the patients on the 7.5 mg/kg dose and two of the patients on 5 mg/kg dose showed improvement. Although there was not a statistically significant difference between the treatment groups and placebo, the study was underpowered and suggests that infliximab may be beneficial in some patients.

Inclusion-body myositis. In contrast to dermatomyositis and polymyositis, there is no effective treatment for inclusion-body myositis. Despite many attempts with steroids, azathioprine, methotrexate, mycophenolate, or cyclosporine, a successful therapy has not yet been found. Three different placebo-controlled trials with intravenous immunoglobulin alone or in combination with prednisone found a slight improvement in muscle strength that did not reach statistical significance (81). Alemtuzumab, a T cell depleting monoclonal antibody, has significantly slowed down progression for a 6-month period in a small uncontrolled study, but no substantial improvement in strength was detected (42). In two separate open-label studies, bimagrumab (a monoclonal antibody against transforming growth factor receptor), and gene therapy with follistatin (a myostatin inhibitor) both increased lean muscle mass and improved muscle function as measured by the 6-minute walk test, although there was no impact on quadriceps strength (08; 109). Furthermore, there was no evidence of clinical benefit seen with bimagrumab in a 2-year extension study (07).

Necrotizing myopathies. This group of inflammatory myopathies has received increased attention in recent years. Although there are no randomized trials evaluating specific treatment options in necrotizing myopathies, in general, patients tend to only partially respond to immunotherapy (63). In many cases, the treatments seem to stabilize rather than improve the disease. Treatment should be based on the underlying cause of the myopathy. For instance, if a tumor is present, tumor removal is mandatory. If the disease is associated with statin treatment, withdrawal of these drugs can improve the muscle weakness although most patients require long-term immunosuppressive therapy. According to an expert panel consensus statement, first-line treatment consists of intravenous/oral corticosteroids followed by a second-line agent (commonly methotrexate, although rituximab may be used in the case of anti-SRP myopathy) within the first month (06). For patients with anti-HMGCR myopathy, IVIG can be added in lieu of methotrexate or together in severe cases. If methotrexate is not tolerated, azathioprine or mycophenolate mofetil, can be used instead. For refractory cases, plasma exchange, cyclophosphamide, or cyclosporine may be considered (06). A Mayo Clinic review found that most patients require at least two immunosuppressive agents (86).

Concluding remarks

Many different trials have demonstrated the beneficial effects of immunosuppressive and immune-modulating drugs in autoimmune neuromuscular diseases. However, most treatments lack Level I evidence derived from randomized trials. Two factors influence a relative stagnation in classic therapies and the scarcity of trials with new drugs: (1) the incomplete knowledge of pathogenesis and (2) the favorable response to classic drugs seen in most patients.

Further understanding of the pathogenesis of these diseases should guide the use of new therapies and provide more specific and effective treatments for the future.