Neuroimmunology in Clinical Practice - part 7 pps

Autoimmune myasthenic syndromes 159 Immunotherapy Immunotherapy is necessary for most patients with MG and is generally more effective than symptomatic therapy. Immunotherapy targets the autoimmune pathophysiology: either by reducing pathogenic antibody production or by reducing damage to the end plate caused by pathogenic antibodies. Immun- otherapies in MG can be divided into two groups based on their onset and duration of response: those that provide rapid improvement but have short-lived benefits; and those that have relatively slower onset but provide long-term benefits. The therapeutic responses of the various therapies dictate their strategic use in the treatment of patients with MG. Long-term immunotherapy Thymectomy Thymectomy has two roles in the management of MG. Thymectomy is indicated for all patients with thymoma in order to prevent local spread and invasion of the tumor. Thymectomy also is an accepted therapy for nonthymomatous MG. The rationale is based on the presumed role of the thymus gland in the initiation and/or maintenance of the immune dysfunction in MG. Numerous studies give support for beneficial effects of thymectomy on the clinical course of MG. An evidenced-based review of 21 studies conducted between 1953 and 1998 found that thymectomy led to clinical improve- ments and two times the likelihood of achieving a medication-free clinical remission (Gronseth and Barohn, 2000). The onset of benefit tends to occur 6 to 12 months following surgery, and the maximal benefit may require 2 to 5 years (Masaoka et al., 1996). Unfortunately, all studies have suffered from significant confounding factors: none were randomized, many were not controlled. Thus, significant limitations and controversies exist regarding their interpretations. Currently, most practitioners consider thymectomy more effective if performed within the first years of symptom onset for patients who are younger (usually less than 60 years old), and if more invasive and “complete” operative procedures are performed (Durelli et al., 1991; Maggi et al., 1989). Seronegat- ive patients may benefit from thymectomy but small retrospective series suggest that anti-MuSK positive patients may not benefit from thymectomy (Sanders et al., 2003). The therapeutic response to thymectomy may not be as favorable for patients with thymoma compared to patients with thymic hyperplasia, but the myasthenic symptoms of thymoma-related MG are similarly responsive to medical therapy. Immunosuppressants Corticosteroids (usually prednisone) are the most commonly used form of maintenance immunotherapy in patients with MG. Steroids have numerous immunosuppressive effects on the immune system. They provide a reliable and rapid onset of action, but produce the most side effects of the immunosuppressive therapies. They are typically indicated for patients whose symptoms respond inadequately to AChE inhibitors and are significantly disabling or in danger (i.e., have respiratory or bulbar weakness) so as to warrant the high risk of side effects that occur with chronic steroid use. Prednisone can be initiated at 60 to 100 mg per day with the expectation of an initial response within two to four weeks and a maximal response in about six months. With this regimen, transient steroid-induced weakness can occur in about one-third of patients. Lower dose, slowly escalating regimens reduce this risk but take longer to induce a response. After adequate improvement is achieved, the dose should be minimized very slowly and cautiously. Aggressive measures should be taken to prevent and monitor for the side effects common to chronic steroid use. Several immunosuppressant drugs are commonly used in the management of MG. These therapies typically take a few months to achieve a response, and many more months to reach maximum benefit. They are usually employed in combination with corticosteroids as steroid-sparing agents or to produce a greater response than corticosteroids alone. Patients who are mildly disabled and stable enough to wait several months for treatment effect may be able to use immunosuppressant monotherapy. Patients who tolerate corticosteroids poorly, such as diabetics or patients with gastric ulcer disease, also may benefit from this option. While side effects can occasionally be significant, they are usually better tolerated than long-term corticosteroid therapy. Azathiopurine is a general immune suppressant that is beneficial for MG (Kuks et al., 1991). This purine analog inhibits DNA synthesis and thus reduces T- and B-cell proliferation. Its onset of action takes a few months, with maximal benefit sometimes requiring up to one to two years. Mycophenolate NICP_C09 04/05/2007 12:25PM Page 159 160 ANDREW SYLVESTER AND ARMISTEAD WILLIAMS mofetil is becoming increasingly popular due to its efficacy and favorable side-effect profile (Meriggioli et al., 2003). Its predominant action is blocking purine synthesis selectively in activated T and B lymphocytes by blocking the de novo pathway of purine synthesis upon which only lymphocytes rely. Patients sometimes show improvement within two months (Ciafaloni et al., 2000) but typically require many more months to achieve maximum benefits. Cyclosporine A is an immunosupressant that blocks interleukin-2 activation of T-helper cells by inhibiting calcineurin. While a controlled, double-blind clinical trial has shown its effectiveness in MG (Tindell et al., 1993), significant side effects and drug interactions usually render it less preferable than azathioprine and mycophenolate mofetil for most patients. Onset of action is often four to eight weeks, with benefits increasing over many months. Other immunosuppressive agents sometimes considered for severe treatment-resistant MG patients include cyclophosphamide (Gustavo De Feo et al., 2002), tacrolimus (Evoli et al., 2002), and rituximab (Zara et al., 2000). Short-term immunotherapy The two short-term immunotherapies used in the treatment of MG are plasmapheresis (therapeutic plasma exchange) and intravenous immunoglobulin (IVIg). These treatments have a rapid onset of action, usually within one week, and short durations of benefit, usually between one and two months. They are used in four clinical settings: 1 in myasthenic crisis or severe exacerbations to produce rapid improvement; 2 prior to surgery (including thymectomy) in order to maximize strength and reduce postoperative morbidity; 3 as bridging therapy for treatment-resistant MG or steroid-intolerant patients, administered every month or so until slow-onset long-term therapy takes effect 4 when initiating corticosteroid therapy to minimize the risk of transient steroid-induced weakness. The efficacy of plasmapheresis has been demonstrated in several uncontrolled studies (Pinching et al., 1976, 1977). Plasma exchanges typically remove one to two plasma volumes roughly every other day for a total of five to six treatments. The mechanism of action of plasmapheresis is the bulk removal of pathogenic antibodies and immune complexes. Small series of patients with anti-MuSK antibodies report good response to plasmapheresis (Evoli et al., 2003). With IVIg, polyclonal human Ig is administered at 2 g/kg over two to five days. Efficacy has been demonstrated in several nonplacebo-controlled studies (Arsura, 1989; Cosi et al., 1991). While IVIg is known to have numerous effects on the immune system, those responsible for the therapeutic response in MG have not been established. A randomized study comparing IVIg to plasmapheresis showed equal efficacy, but IVIg had fewer and less severe side effects (Gajdos et al., 1997). Lambert–Eaton myasthenic syndrome Introduction Lambert–Eaton syndrome (LES) is a rare disease that causes fatigable muscle weakness and mild autonomic dysfunction. It is caused by an immune-mediated attack against the voltage-gated calcium channels (VGCC) on the presynaptic motor nerve terminal. In about 40–50% of patients, LES occurs as a paraneoplastic syndrome (P-LES), usually associated with small-cell lung cancer (SCLC). Although paraneoplastic syndromes are rare in neurology, LES is the most common and one of the best characterized. Nonparaneoplastic LES (NP-LES) accounts for approximately 50–60% of LES cases and occurs as an idiopathic autoimmune disease of unknown etiology. History In 1953, Anderson and colleagues described a patient with oat cell lung cancer who had myasthenic symptoms (Anderson et al., 1953). From 1956 to 1961, Lambert and his colleagues described a series of patients who suffered from fatigable muscle weakness that differed from myasthenia gravis. These patients had a different distribution of weakness, areflexia, and autonomic dysfunction. Their neuro- physiological profile was also distinctive with facilitation of both muscle strength after exercise and the amplitude of compound muscle action potential (CMAP) after high-frequency repetitive electrical stimulation (Eaton and Lambert, 1957; Lambert et al., 1956, 1961). In most of these patients (10 out of 17), their myasthenic syndrome was associated with malignancies, especially small-cell lung cancer. Elmqvist and Lambert were the first to identify that the pathophysiology of LES involved dysfunction NICP_C09 04/05/2007 12:25PM Page 160 Autoimmune myasthenic syndromes 161 of the presynaptic motor nerve terminal with reduction of quantal release of acetylcholine (Elmqvist and Lambert, 1968; Lambert and Elmqvist, 1971). In 1972, Gutmann noted an association of autoimmune disorders in patients with LES without malignancies, and theorized an autoimmune etiology for LES (Gutman et al., 1972). The autoimmune basis for LES was supported by the development of clinical and physiological features of LES in mice receiving IgG from patients with LES (Fukunaga et al., 1983; Kim, 1986; Lambert and Lennon, 1988; Lang et al., 1981), the discovery that serum IgG from patients with LES interacts with VGCC in cell cultures of human small-cell carcinoma (Roberts et al., 1985), and, in 1989, the development of a diagnostic radio- immunoassay that binds the pathogenic VGCC- directed autoantibodies in LES (Lennon and Lambert, 1989). Based on its known pathophysiology, several treatments have been developed that positively impact the lives of patients with LES. These treatments include those that enhance the release of acetylcholine from the presynaptic motor nerve terminal, plasmapheresis, IVIg, and immunosuppressive medications, as well as surgical removal of associated malignancies. Clinical features The characteristic clinical presentation of patients with LES consists of subacute progressive proximal limb muscle weakness and fatigability, diminished or reduced muscle stretch reflexes, and autonomic dysfunction. The diagnosis is often delayed for months or even years because the symptoms often begin insidiously and findings on physical examination may go undetected early in the course of the disease. The typical distribution of weakness involves the hip flexors and other hip girdle muscles, the proximal muscles of the upper extremity, neck muscles, and the interossei muscles. The hip girdle muscles usually are affected more prominently than those of the upper extremities, and account for the majority of disability. In one series of 50 patients, weakness began in the lower limbs in 65% (O’Neill et al., 1988); 12% began with generalized weakness, but with hip girdle muscles involved more than other muscles of the body. Patients often complain of difficulty arising from a sitting position and climbing stairs, and sometimes even fall. Patients commonly report that the weakness transiently worsens on repeated muscle exertion and improves with rest. Occasionally, patients experience transient improvement of strength following brief exertion, followed by increasing weakness with continued exertion; eliciting this history, though, is not common. Muscle atrophy is rare. Enhance- ment of depressed reflexes after brief exercise or repeated elicitation of the reflex is strongly sug- gestive of the diagnosis and is more readily demonstrated at the bedside than facilitation of muscle strength. Patients may experience aching pain in their hips and posterior thigh. Approximately 25% have cranial nerve involvement. Ptosis, facial weakness, dysphagia, dysarthria, and difficulty chewing can occur but are usually milder and tend to occur later in the disease course than in MG. Respiratory involvement is less common and usually significantly milder than in MG. Respiratory failure is rare. Approximately 80% of patient with LES have symptoms of autonomic dysfunction. In 6%, autonomic dysfunction is the presenting symptom (O’Neill et al., 1988). The most common autonomic symptoms are erectile dysfunction in men and xerostoma (dry mouth) in both sexes. Other features include slow pupillary reaction to light, gastrointestinal dysmotil- ity, orthostatic hypotension, and urinary retention. Autonomic testing may reveal abnormalities in sweat- ing, cardiovagal reflexes, and salivation. As mentioned earlier, early medical description noted a clear association of malignancy in approximately 40–50% of patients diagnosed with LES. The majority of the patients had small-cell lung cancer (SCLC). While several other types of cancer have been reported in patients with LES, only lymphoma has shown a possible paraneoplastic association with LES. The symptoms of LES can precede the diagnosis of malignancy by several years, but not usually more than five years. Symptoms of lung cancer itself are uncommon at the time of diagnosis of LES. The sensory system is always spared in LES. If sensory deficits are present, their origin may lie in the presence of an additional paraneoplastic disease such as sensory neuronopathy, peripheral neuropathy, or myelopathy. Other paraneoplastic syndromes associated with LES include subacute cerebellar ataxia and encephalo- myelitis. Organ-specific autoimmune diseases such as pernicious anemia and autoimmune thyroid disease are common in patients with NP-LES. Natural history The course of LES tends to be slowly progressive in the first year. Fluctuations of symptoms are less pronounced and spontaneous remissions are less common than with MG. The course of NP-LES can vary considerably. Approximately half of NP-LES NICP_C09 04/05/2007 12:25PM Page 161 162 ANDREW SYLVESTER AND ARMISTEAD WILLIAMS patients achieve sustained remissions, usually with chronic immunotherapy but sometimes spontan- eously (Maddison et al., 2001). The other half suffers various degrees of long-term disability. Immuno- therapy is effective in reducing disability, however, less so than with MG. In patients with P-LES, the course may be more heterogeneous compared to those with NP-LES. The symptoms of P-LES often improve following effective treatment of the underlying cancer, with 70% of patients achieving clinical remission (Chalk et al., 1990; Maddison et al., 2001). The overall prognosis for these patients is related to that of the underlying cancer, which for SCLC is usually fatal. One report notes SCLC in patients with LES tends to be less aggressive and has a greater response to therapy than patients without LES (Maddison et al., 1999). When coexisting paraneoplastic syndromes of peripheral neuropathy and subacute cerebellar ataxia occur, their symptoms tend to be more prominent and disabling than LES. Epidemiology Figures for the incidence and prevalence of LES are unknown due to its rarity. Idiopathic LES occurs more often in females and can occur at any age (Maddison et al., 2001). There is a frequent association with organ- specific autoimmune disorders in these patients and family members. Certain HLA-gene products are found in higher prevalence than in patients with P-LES (Parsons et al., 2000; Willcox et al., 1985). P-LES occurs more often in men and in older populations at higher risk of cancer. Cancer is found in 45% of patients with LES, with SCLC accounting for 90% (O’Neill et al., 1988). Other cancers reported include lymphoproliferative disorders, thymoma, renal cell cancer, and tumors of the reproductive tract (Argov et al., 1995; Burns et al., 1999; Collins, 1999; Gutmann et al., 1992; O’Neill et al., 1988; Oyaizu, 2001). Occasionally patients with these cancers harbor occult SCLC as well. Primary small- cell carcinoma of extrapulmonary locations can occur in patients with LES, especially when no risk factors for lung cancer are present. In patients with SCLC, LES occurs in approximately 6% (Croft and Wilkinson, 1965; De La Monte et al., 1984; Hawley et al., 1980). Eighteen percent of patients with SCLC are seropositive for antibodies to the P/Q-type calcium channel without clinical evidence of LES. Pathophysiology The Lambert–Eaton myasthenic syndrome is an immune-mediated disease caused by antibodies directed at the α 1A subunit of the VGCC located on the presynaptic nerve terminal. As described in the pathophysiology section on myasthenia gravis, a nerve impulse induces presynaptic calcium influx via VGCCs, which triggers the release of acetylcholine into the synaptic cleft. Electrophysiological studies of LES patients show a presynaptic abnormal- ity in neuromuscular transmission (Lambert et al., 1961). The miniature end-plate potentials (MEPP) have normal amplitude and frequency in LES. There is a reduced number of ACh vesicles released, leading to a reduction of end-plate potential (EPP) amplitude. This produces a decrease in the safety margin of neuromuscular transmission. High-frequency repetitive nerve stimulation or bathing a muscle sample in high-calcium solutions increases the EPP amplitude. These features support the concept that VGCC antibodies in LEMS patients reduce calcium flux through VGCCs on the presynaptic membrane. While the specific disruptive mechanism or mechanisms of these antibodies requires further study, significant evidence implicates VGCC antibodies that bind and cross-link adjacent VGCCs. This causes an acceleration in the rate of VGCC degradation, known as antigenic modulation (Fukuoka, 1987; Prior, 1985). This reduces the number of available VGCCs. This process is IgG-mediated, and does not involve complement. Significant ultrastructural abnormalities occur in the presynaptic membrane in patients with LES that further reduce the safety margin of neuromuscular transmission. Several types of VGCC exist which are distinguished by differences in their biomolecular and pharmacological properties. The P/Q-type VGCC are normally arranged in parallel arrays in the active zones of the presynaptic motor nerve terminal and some preganglionic autonomic synapses. Most patients with LES have antibodies directed at the P/Q-type VGCC. In patients with LES, there is a reduction in the density of active zones in the motor nerve terminals and the normally formed parallel arrays of P/Q-type VGCCs become disordered (Fukunaga et al., 1982). These anatomical changes reduce the number of functional calcium channels leading to a decrease in the release of acetylcholine. The autonomic symptoms involved in LES may be mediated by a similar immunological process (Waterman, 2001). The neurons of the autonomic nervous system contain a different array of VGCCs. The subtype of VGCCs varies among specific tissues and the neurotransmitters utilized. The predominant NICP_C09 04/05/2007 12:25PM Page 162 Autoimmune myasthenic syndromes 163 subtype found in the autonomic nervous system is the N-type VGCC, but P/Q-type and R-type VGCCs are present to lesser degrees. Autoantibodies from patients with LES may impair neurotransmitter release through downregulation of one or more subtypes of VGCCs at the presynaptic sympathetic and parasym- pathetic autonomic nerve terminal. This inhibition of autonomic nervous system transmission likely is the basis for their autonomic symptoms. Interestingly, most patients with autonomic symptoms in LES do not possess antibodies to the N-type VGCC, whereas the majority possess antibodies to the P/Q-type receptor. The degree of autonomic dysfunction does not seem to correlate with the presence of the P/Q-type or the N-type VGCC. In P-LEMS, evidence supports the hypothesis that antigens expressed on the underlying neoplasm may provoke and maintain the autoimmune response towards the VGCCs. First, P/Q-type VGCCs are expressed in SCLC cells (McCann et al., 1981; Roberts et al., 1985). Immunoglobulins obtained from LEMS patients with SCLC bind to P/Q-type VGCCs and produce downregulation of these channels in SCLC cells. Patients with LEMS often experience improve- ments in muscle strength with effective treatment of the underlying cancer. This evidence suggests that VGCCs on the SCLC cells trigger an autoimmune process in which pathogenic antibodies cross-react with VGCCs on the SCLC cells and the presynaptic nerve terminals. In NP-LES, the etiology of the autoimmune dysregulation has not been elucidated. Patients with NP-LES are known to have an increased frequency of autoimmune disease and autoantibodies in their personal or family history compared to patients with P-LES (Lennon et al., 1982; O’Neill et al., 1988). Clinically, no major features differ between NP-LES and P-LES except the age and sex differences noted above and the presence of P/Q-type VGCCs is more commonly found in P-LES. While an immune- mediated process has been established as the cause, the primary cause of this immune dysregulation has not been found. Diagnosis Clinical manifestations The basis for the diagnosis of LES is the clinical triad of fatigable proximal limb muscle weakness, reduced or absent muscle stretch reflexes, and autonomic dysfunction. Ancillary tests for LES are distinctive and usually provide reliable confirmation of the diagnosis. Cases of prolonged apnea following surgery with exposure to neuromuscular blocking agents should prompt suspicion of LES (as well as MG). LES should also be considered in patients with another lung cancer associated paraneoplastic syndrome who develop significant weakness or have antibodies to the P/Q-type calcium channel. Sometimes LES is diagnosed in patients previously misdiagnosed with seronegative MG. Electrodiagnostic studies Electrodiagnostic studies provide the most specific and rapid confirmation of the diagnosis of LEMS. The distal hand muscles often provide the most pronounced findings. CMAPs have a low amplitude at baseline. CMAPs display a decremental response at slow rates of repetitive nerve stimulation and marked postactivation facilitation of greater than 100–200% following high-frequency repetitive nerve stimulation (at rates of 20–50 Hz) or about 10 seconds of brief exercise (Harper, 1999). Single-fiber electromyography demonstrates increased jitter and blocking that transiently improve with high firing rates. This combination of findings is the hallmark of LES. Serum testing Antibodies directed towards the P/Q-type VGCC are detectable in greater than 90% of patients with LES (Lennon et al., 1995). In LES patients with SCLC, up to 100% have antibodies to VGCC, whereas 50–90% of LES patients without associated cancer have antibodies to VGCC. In P-LEMS, antibodies directed to the N-type VGCC are present in 75% of patients with SCLC and generally not seen in patients with other types of cancer. Forty percent of NP-LES have antibodies to the N-type VGCC. Antibody titers tend to diminish with improving disease severity, the administration of immunotherapy, and effective treatment of an underlying malignancy. It is, thus, imperative to test for VGCC antibodies early in the evaluation of all patients under consideration for LES. The interpretation of positive serum antibody tests requires correlation with the clinical picture. Anti- bodies to VGCC can occur in other conditions not in association with clinical LEMS. In SCLC patients without LEMS, 18% have P/Q-type VGCC antibodies and 22% have N-type VGCC antibodies. VGCC antibodies occur in 15–40% of patients with paraneoplastic cerebellar ataxia, and rarely in autoimmune NICP_C09 04/05/2007 12:25PM Page 163 164 ANDREW SYLVESTER AND ARMISTEAD WILLIAMS MG or other autoimmune disorders (Yu et al., 2001). In 13% of patients with LEMS, muscle or ganglionic nicotinic AChR antibodies or striational antibodies are present. Differential diagnosis While the characteristic clinical features of LES are quite distinctive, LES is frequently misdiagnosed initially due to its insidious onset and rarity. The differential diagnosis of LES includes such disorders as MG, myopathies, polymyalgia rheumatica, and botulism. Several features distinguish LES from these disorders. With MG, the distribution of weakness and fatigability with early involvement of ocular and bulbar muscles, as well as typical electrodiagnostic and autoimmune serological profile differentiate it from LES. Myopathies may present with a similar distribution of weakness. However, the lack of autonomic dysfunction, different electrodiagnostic findings, and reflexes which are proportional to the degree of weakness and do not exhibit potentiation after brief voluntary exertions, distinguish them from LES. Botulism causes progressive weakness, autonomic dysfunction, and some similar electrodiagnostic features. The course, however, is more fulminant, and prominent respiratory involvement, early pupillary involvement, and a descending progression of weakness are not typical features of LEMS. Polymyalgia rheumatica can present with muscle pain, but an elevated erythrocyte sedimentation rate (ESR) and the lack of true muscle weakness and fatigability differentiate it from LEMS. Treatment and management Once the diagnosis of LES has been established, an extensive investigation for an underlying malignancy should be implemented. For patients with an underlying malignancy, symptoms of LES often improve with treatment of the malignancy. If the evaluation detects no malignancy, repeated testing should be performed at regular intervals for at least five years, especially in persons with significant risk factors for cancer. In patients with P-LES, treatment should be directed towards the underlying malignancy. Patients in whom the underlying malignancy is not effect- ively treated tend not to improve substantially with immunotherapy. Conversely, effective treatment of the underlying malignancy usually leads to significant improvement of the neurological symptoms, and, in some cases, to complete remission. Some of these patients may not require further treatment for LES. Immunotherapy should be considered for patients whose malignancies respond to therapy but their neurological symptoms not improve adequately. It is also indicated for patients without malignancy who suffer from significant disability despite symptomatic therapy. Therapy of LES must be indi- vidualized, with consideration given to the degree of disability, associated underlying medical conditions, and life expectancy. The therapeutic strategies for immunotherapy are generally similar to those used with MG, although the response to treatment is often less dramatic. Symptomatic treatment 3,4-Diaminopyridine (3,4-DAP) has been shown to improve symptoms in patients with LES in placebo- controlled prospective trials (Lundh, 1990; McEvoy, 1989). Many practitioners consider 3,4-DAP first- line therapy for LES. 3,4-DAP blocks voltage-gated potassium channels in the nerve terminal, which leads to prolongation of the action potential and opening of VGCC, increased calcium entry and, ultimately, to enhanced ACh release. Dosing schedules vary, and repeated dosages are titrated to optimize patient response (Lundh et al., 1993; Sanders, 1998). 3,4- DAP is usually well tolerated but it is not approved for clinical use in the United States. Thus, it is available only for compassionate use as an investiga- tional drug. Guanidine hydrochloride also enhances the release of ACh from the presynaptic nerve terminal. Guanidine increases calcium within the nerve terminal by inhibiting uptake of calcium by subcellular organelles (Kamenskaya et al., 1975). While guanidine is occasionally utilized in the management of LES, its use has been significantly limited due to potential hematopoietic and renal toxicity. Cholinesterase inhibitors are sometimes administered in LES. Potential benefits are limited, perhaps because it is an attempt to slow the metabolism of an already-reduced amount of ACh. Clinically, CIs are not particularly effective as monotherapy. Enhanced benefits can occur when CIs are combined with medications that facilitate the release of acetylcholine, such as the 3,4-diaminpyridine or guanidine. Immunotherapy For patients who fail to respond adequately to symptomatic treatments, immunotherapy is an option. NICP_C09 04/05/2007 12:25PM Page 164 Autoimmune myasthenic syndromes 165 Therapeutic plasma exchange and IVIg are both used for short-term immunotherapy because they provide relatively quick onset but short-term benefits (Bain et al., 1996; Newsom-Davis and Murray, 1984). Clinical response to plasma exchange occurs around 10 days and for IVIg around 2 weeks, somewhat slower than with MG. The benefit of both lasts about 6–8 weeks. Plasma exchange and IVIg both are typically utilized for patients with severe weakness, or bulbar or respiratory muscle involvement. Repeated treatments sometimes have been employed for maintenance therapy or until long-term immunotherapy takes effect. Patients with long-standing disabling symptoms should consider chronic immunosuppressive therapy. In patients with known malignancy or at high risk for malignancy, it is important to be contemplative of the theoretical risk of immunosuppression pro- moting tumor growth. Although not considered high risk, some practitioners reserve immunosuppressive therapy only for the most disabled patients who fail to respond to other therapies. Prednisone is often the choice immunosuppressive (Lundh et al., 1990). It is administered at dosages of 0.75–1 mg/kg/day, typically 60–80 mg per day. After clinical response occurs, the dosing schedule may be converted to alternate days (i.e. 100–120 mg every other day). Starting on alternate-day dosing usually delays the onset of the clinical response. The dose of prednisone should be gradually tapered over many months to the minimal dose required for adequate disease control. The administration of an additional immunosuppressive agent may help minimize steroid exposure and is usually better tolerated than steroids. Azathioprine is often utilized and has shown benefit in this role in a retrospective study (Lee et al., 2001). Azathioprine also can be used as monotherapy for those patients who can wait months for clinical response. The therapeutic efficacies of mycophenolate mofetil, cyclosporine, and other immunosuppressive agents have not been adequately investigated for use in patients with LES. 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NICP_C09 04/05/2007 12:25PM Page 168 [...]... directed against aminoacyl-transfer RNA synthetase (antisynthetases), antibodies directed against signal recognition particle proteins (anti-SRP), and antibodies directed against the nuclear protein complex Mi-2 (anti-Mi-2) The antisynthetases are the most common MSAs, with anti-SRP and anti-Mi-2 occurring considerably less often The presence of MSAs appears to be associated with a particular clinical subset... understanding of disease mechanisms in the idiopatic in ammatory myopathies? Curr Opin Rheumatol, 16, 70 7–13 NICP_C10 03/05/20 07 10:38 AM Page 177 Polymyositis and dermatomyositis Dalakas, M.C 1991 Polymyositis, dermatomyositis, and inclusion-body myositis N Engl J Med, 325, 14 87 98 Dalakas M.C 2002 Muscle biopsy findings in inflammatory myopathies Rheum Dis Clin North Am, 28, 77 9–98 Dalakas, M.C 2004 In ammatory... 183 Neuro-Sjögren’s syndrome and activation of the in ltrating, predominantly CD4 lymphocytes The presented antigens include SSA (Ro), SSB (La), α-fodrin, β-fodrin, and muscarinic cholinergic receptors The helper T-cell activation leads to B-cell stimulation and antibody production Anti-SSA may occur alone, while anti-SSB is usually present in association with anti-SSA An association of P-SS with the... fatty in ltration (Adams et al., 1995) MRI may be helpful in identifying “occult” muscle disease or to aid in localizing an active site for potential biopsy to optimize the yield of obtaining a meaningful biopsy result It also may be helpful in distinguishing active in ammation from atrophy The MRI techniques used include T1and T2-weighted images with T2 being sensitive for detecting muscle edema in acute... progress in polymyositis, dermatomyositis and inclusion body myositis Curr Opin Neurol, 175 61 7 Dalakas, M.C 2005 Intravenous immunoglobulin in patients with anti-GAD antibody-associated neurological diseases and patients with in ammatory myopathies Effects on clinicopathological features and immunoregulatory genes Clin Rev Allergy Immunol, 29, 255–68 Dalakas, M.C 2006 The role of high-dose immune globulin... malignancy and interstitial lung disease Anti-Jo-1 antibodies are rarely found in CADM patients even if they have interstitial lung disease The other interesting finding in this review is that in adult-onset CADM calcinosis is very uncommon Juvenile dermatomyositis differs from the adult form both histologically and clinically (Pachman and Dooke, 1980; Reed and Mason, 2005) The histological finding on muscle... Peter (1 975 ) was published In their description of the disease they ascribed the probability of having the disease based on a number of clinical features being present (Box 10.1) New efforts in further defining the disease have included exhaustive search for myositisassociated antibodies and pathological findings Bohan and Peter’s criteria have been criticized for being inadequate in excluding other... time A variety of steroid-sparing agents have been tried including azathioprine, methotrexate, cyclosporine, cyclophosphamide, mycophenolate (Edge et al., 2006; Majithia and Harisdangkul, 2005), and tacrolimus (Mitsui et al., 2005) High-dose intravenous immunoglobulin (IVIg) infusions as treatment for dermatomyositis have been shown to be beneficial in a placebo-controlled double-blind randomized trial... G 2001 Incidence of malignant disease in biopsy-proven myopathy Ann Intern Med, 134, 10 87 95 Chiappetta, N., Steier, J and Gruber, B 2005 Rituximab in the treatment of refractory dermatomyositis J Clin Rheumatol, 11, 264–6 Childs, N.D 19 97 STIR-MRI goes past fat to detect myopathies Intern Med News, 1, 37 Chinoy, H., Ollier, W.E and Cooper, R.G 2004 Have recent immunogenetic investigations increased... normal imaging is not rare even in cognitively affected patients Spinal imaging in patients with spinal cord syndromes usually reveals abnormalities compatible with transverse myelitis, myelopathy, or discrete MS-like lesions (Fig 11.1) 183 Treatment High-dose corticosteroids have been used in acute exacerbations and low-dose steroids in chronic stages of P-SS In progressive cases, azathioprine, cyclophosphamide, . T-helper cells by inhibiting calcineurin. While a controlled, double-blind clinical trial has shown its effectiveness in MG (Tindell et al., 1993), significant side effects and drug interactions. terminal. Guanidine increases calcium within the nerve terminal by inhibiting uptake of calcium by subcellular organelles (Kamenskaya et al., 1 975 ). While guanidine is occasionally utilized in. disease. Anti-Jo-1 antibodies are rarely found in CADM patients even if they have interstitial lung disease. The other interesting finding in this review is that in adult-onset CADM calcinosis is

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