Treatment and Management of Disorders of the Neuromuscular Junction

Steroids

In a large nonrandomized study, remission or marked improvement was reported in 63%–82% of GMG and in 66%–86% of OMG patients treated with oral corticosteroids, usually prednisone (class IV evidence) ( ) ( Table 19.2 ).

The efficacy has been established in double-blind, placebo-controlled trials with methylprednisolone but not with prednisone. A randomized trial compared double-blind IV methylprednisolone (10 patients) versus placebo (9 patients) for GMG ( Table 19.3 ). The steroid group showed a 7.2 times greater improvement in muscle strength than the placebo group did after 2 weeks of treatment, indicating a significant short-term benefit from steroid. A randomized, double-blind trial of prednisone (six patients) versus placebo (seven patients) for GMG showed no significant difference in improvement at 6 months. This study lacks credence because of the small number of patients for each group. In a randomized controlled trial with methylprednisolone vs. IV immunoglobulin (IVIg), no significant difference was noted at day 14, indicating that methylprednisolone is as good as IVIg. Thus, steroids are useful as short-term immunosuppressants (class II). Long-term use of steroids is associated with many adverse effects, including weight gain, fluid retention, diabetes, psychosis, glaucoma, cataracts, gastrointestinal (GI) bleeding, and osteoporosis. Steroids should be used ideally as short-term (60 mg/day for 3–4 months) immunosuppressants. However, long-term use of a steroid is not unusual. The risk of osteoporosis is reduced by giving bisphosphonates (class IV).

Oral prednisone is recommended as the first drug of choice when immunosuppressive drugs are necessary in MG (class IV). This is because steroid is known to induce the earliest onset of improvement among the various immunosuppresants. Controversy exists regarding the most prudent method of initiating therapy (high-dose daily, high-dose alternate day [AD] or low-dose AD, with a gradually increasing regimen). Low doses (20–30 mg) are recommended by those who believe that some patients develop steroid worsening, including MG crisis, in 4 to 10 days on higher doses (class IV) ( Table 19.4 ). The low dose is gradually increased to a high dose over a period of a few weeks. High doses (>60 mg/day) are recommended by others, including this author, who believe that improvement is more rapid with high-dose daily regimens and steroid worsening represents natural worsening of MG because we start steroid in patients with unstable MG. I personally believe that steroid worsening is exaggerated and extremely rare these days since we use a smaller daily dose of AChEIs. Thus, I recommend an initial high-dose regimen unless there is any compelling reason not to do so. Once the maximal benefit or pharmacological remission is achieved, owing to the potential adverse effects with prolonged use of steroids, the dose should be slowly reduced to the minimum effective maintenance dose or withdrawal and the simultaneous use of a long-term immunosuppressant are initiated.

Azathioprine

Azathioprine (AZA) is extensively used as immunosuppressive. The onset of therapeutic response may be delayed for 4–10 months, and maximal effect is obtained in 1–2 years. AZA is usually well tolerated, but idiosyncratic flu-like symptoms or GI disturbances, including pancreatitis, occur in 10%, usually within the first few days of treatment. Side effects include bone marrow suppression and hepatotoxicity, which usually respond to drug reduction or withdrawal. When the white blood cell falls below 4000 mm ³ , the dose should be reduced; if it is below 3000 mm ³ , AZA should be discontinued. The incidence of malignancy was not increased over 22 years of AZA treatment in study.

Several observational series of AZA treatments showed 70%–100% improvement with AZA alone or in combination with other treatments, mostly with steroids (class IV) ( ). One study comparing early high-dose immunosuppressive with AZA and prednisone resulted in 50% of patients achieving remission after 2 years, compared with a remission rate of only 16% in those on a low-dose regimen.

One large double-blind randomized study ( ) has demonstrated the efficacy of AZA as a steroid-sparing agent with a better outcome in patients on a combination of AZA and steroids than in patients treated with steroids alone (class I). In a randomized, unblinded trial of AZA plus initial prednisone versus prednisone alone, no difference was found in remission or marked improvement between two groups in 1–3 years of long-term treatment.

Because AZA has been associated with relatively few treatment failures and steroid-sparing effect in two randomized controlled trials (class I), we do recommend AZA as the first-choice long-term immunosuppressant drug. Some prefer to start AZA together with steroids to allow tapering of steroids to the lowest dose possible. The usual recommended daily dose is 150 mg/day.

Cyclosphosphamide

In one observational study in 42 patients who were given cyclophosphamide (CPP) with a duration of treatment from 2 to 37 months, remission was achieved in 58% of patients who underwent 1 year of treatment, 85% of patients who underwent 2 years of treatment, and 100% of patients who underwent 32 months of treatment ( ). In a randomized, double-blind trial of CPP plus prednisone versus prednisone plus placebo in GMG, CPP significantly improved muscle strength at 12 months, but not at 6 months ( ). The CPP-treated patients were on significantly lower doses of prednisolone at 6 and 12 months. Thus, this study showed that CPP is clinically effective in GMG and that it has a steroid-sparing effect (class II). The usual oral dose of CPP has been 5 mg/kg/day (usual initial dose, 150 mg/day). CPP can be given as monthly pulse therapy at an IV dose of 1 gm/m ² /month. High-dose CPP (50 mg/kg/day for 4 days) followed by granulocyte colony stimulating factor was also used for “rebooting” of the immune system in refractory MG. In three MG patients refractory to plasma exchange (PE), thymectomy, and conventional immunosuppressants, remission was achieved ( ). In view of the relative high risk of toxicity including bone marrow suppression, opportunistic infections, bladder toxicity, sterility, and neoplasm, this drug is recommended as the last choice of immunosuppressants to patients who are intolerant of or unresponsive to other immunosuppressants. The usual recommended oral daily dose is 150 mg/day.

Cyclosporine A

This is the first agent in MG that showed a definite benefit in a randomized controlled trial. Three observational studies on severe MG unresponsiveness to thymectomy, AZA, or steroid showed marked improvement in 75%–80% of patients in 1–3 years of treatment. One placebo-controlled, double-blind randomized study in 20 patients for 6 months with an open extension (class I) showed significantly improved strength and reduction in AChR antibody titers compared with the placebo group at 6 and 12 months. Another double-blind randomized controlled study with 39 patients showed significantly improved muscle strength at 6 months in the cyclosporine (CsA) plus prednisone group compared with the placebo plus prednisone group, but a steroid-sparing effect was not observed. Thus, two randomized controlled trials have shown that CsA is clinically effective in GMG. Initial daily dose is 4–6 mg/kg/day. However, because of significant side effects such as nephrotoxicity, hypertension, and malignancy, it should be considered only in patients intolerant of or unresponsive to AZA. Other common side effects include hypertrichosis, gingival hyperplasia, myalgia, and “flu-like” symptoms. Nonsteroidal anti-inflammatory drugs should be avoided with CsA because they increase nephrotoxicity. CsA should be considered in patients intolerant of or unresponsive to AZA (level B recommendation). The usual recommended daily dose is 200 mg/day.

Mycophenolate Mofetil

Two open-label trials and two observational studies in MG patients unresponsive to steroid, AZA, or CsA showed 59%–73% improvement over a treatment period of 2–18 months. Improvement occurred in monotherapy as well as with other immunosuppressants. Two randomized, double-blind trials of mycophenolate mofetil (MM) plus steroid versus steroid plus placebo for GMG failed to demonstrate any efficacy of MM in trials of 3 or 9 months’ duration. Another study of a small randomized, double-blind trial of MM plus either CsA or prednisolone or no immunosuppresants versus placebo plus either CsA or prednisolone or no immunosuppressants also did not show any benefit of MM. Although MM has been reported to be not efficacious in randomized controlled trials in GMG, this drug is well tolerated, with a relatively good adverse effect profile ( ),

The adverse effects of MM were usually mild (nausea, headache, or diarrhea). Serious adverse effects such as infections and hematopoietic suppression are rare. One advantage of MM, compared with other immunosuppressants, is a lesser carcinogenic tendency: a kidney transplant patient on MM had a lesser cancer incidence in the long-term follow-up. Lymphoma was reported as a rare complication. The European Task Force recommends MM as the second-line long-term therapy in MG patients intolerant of or unresponsive to AZA (level B recommendation). This view might have to be modified in view of the negative results of two randomized controlled studies. The usual recommended daily dose is 1.5 gm.

Tacrolimus

Although tacrolimus and CsA act in a similar fashion, the potency of tacrolimus appears to be 10–100 times greater than that of CsA. Tacrolimus at 3 mg/day for MG is 20% of the dose given to organ transplant patients. One 4-month open-label study showed an improvement in 37% of cases. Three observational studies with longer than 19 months’ duration showed an improvement in 67%–71% of patients and pharmacological remission in 87% of patients. A randomized, unblinded, non-placebo-controlled trial of tacrolimus plus steroids with or without PE versus no tacrolimus plus steroids with or without PE showed significantly fewer treatments with PE plus high-dose IV methyl-prednisone, a significantly shorter period of early-phase treatment, and significantly lower prednisone dose in tacrolimus-treated groups ( ). Thus, this study showed that tacrolimus reduces the need for other immunotherapy, indicating that this drug is effective in GMG. Tacrolimus seems to be relatively safe at the doses used in MG, so it should be recommended as third-line treatment for patients who are intolerant of or unresponsive to AZA. Common side effects of the drug include hypertension, renal insufficiency, hyperkalemia, headache, and hyperglycemia. If tacrolimus is used in patients with existing impaired glucose intolerance or diabetes mellitus, this impaired glucose tolerance will be almost always exacerbated ( ). The usual recommended daily dose is 3 mg.

Methotrexate

The European Task Force recommends methotrexate as second-line drug because it is well studied in other autoimmune disorders ( ). Two studies reported conflicting results ( ; ). On one hand, Heckmann et al. compared the effect of methotrexate (17.5 mg weekly) versus AZA (2.5 mg/kg daily) in a single-blind study. At 2 years, there was a substantial and comparable decrease in the average daily prednisone dose and in the QMG scores in both groups, suggesting both drugs as effective steroid-sparing agents ( ). On the other hand, in a randomized, double-blind, placebo-controlled trial of methotrexate 20 mg/week by mouth versus placebo in prednisone-dependent MG patients, showed no difference in the prednisone area under the curve between methotrexate and placebo over a 12-month period, suggesting no steroid-sparing effect of methotrexate. We recommend this drug as the last choice if all other immunosuppressants fail or the patient cannot take others. One advantage of this medication is the one-time weekly administration. Initial starting dose is 7.5 mg weekly and maximum weekly dose is 30 mg. The usual recommended weekly dose is 7.5 mg.

Plasma Exchange

PE or plasmapheresis removes antibodies from patient sera by membrane filtration or centrifugation. The patients typically undergo five sessions of PE at 20–50 mL/kg body weight per session over a span of 2 weeks. The plasma is separated from blood cells using membrane filtration or centrifugation, and then the blood cells are reinfused into another vein with diluted albumin, colloids, or crystalloids, while plasma is removed. The onset of improvement is within the first week and the effect lasts for 1–3 months. Side effects are associated with the insertion of the IV catheter and hypotension. Since PE has been extensively used as the treatment of choice in acute MG exacerbation, there is no randomized, double-blind control study for its short-term benefit ( ). There are, however, two nonrandomized controlled studies ( ; ). One study in 1979 compared six patients who received PE over 2 to 2.5 weeks and six patients who were assigned to a control group. None of the control group improved, while all treated patients improved strikingly ( ). Another study in 1979 compared the long-term effect in severe patients treated with PE plus immunosuppressive drugs and seven patients treated with immunosuppressants alone ( ). PE was associated with short-term improvement in all seven patients. At 6 to 12 months, clinical outcome and AChR antibody titer decline were similar in both groups. Many observational studies have shown short-term clinical improvement in 65%–100% of cases. A Cochrane research revealed only one eligible controlled trial ( ; ). The aim of this trial was to compare the long-term effect of prednisone (seven patients) versus prednisone plus PE (seven patients). No difference was found in muscle strength score change at 1 month or 1 year between the two groups. Significantly, there were fewer relapses in the prednisone group. Thus, this trial failed to demonstrate any long-term benefit of prednisone and PE versus prednisone alone ( ). There are several randomized studies comparing the efficacy of PE with IVIg showing comparable therapeutic efficacy ( ; ; ; ). On the basis of these findings, the 1986 National Institutes of Health consensus ( ) is still valid: PE can be useful in strengthening patients with MG before thymectomy and during the postoperative period, and it can also be valuable in lessening symptoms during the initiation of immunosuppressants and during an acute crisis (class IV). Therefore, sham controlled trials would be unethical. A Cochrane review (2008) concluded that there are no adequate randomized controlled trials to establish whether PE improves the long- or short-term outcome from MG, but many case series report short-term benefit from PE in MG, especially in myasthenic crisis (MC) ( ). Repeated PE is thus not recommended as a treatment to obtain continuous and lasting immunosuppression in MG.

Intravenous Immunoglobulin (IVIG)

IVIg is a fractionated blood product consisting primarily of immunoglobulin G (IgG), derived from 3000 to 10,000 human plasma donors. The mechanism of action of IVIg is complex, including almost all aspects of the immune system. The most relevant mechanisms for MG were the neutralizing effect of commercial polyclonal IgG (IVIg) on the blocking effects of myasthenic IgG antibodies to nicotinic AChR and the inhibiting effect on the production of autoantibodies by inhibiting the body’s ability to produce globulin. IVIg is relatively easier to administer than PE. The usual IVIg dose is 0.4–1 gm/kg body weight given over 2–5 days. After infusion, serum IVIg levels increase fivefold, then decline by 50% in 72 hours and return to pretreatment levels after 21–28 days. Severe reactions from IVIg are rare. The most serious reactions so far reported include anaphylactic reaction, hepatitis C outbreak, aseptic meningitis, acute renal failure, hemolysis, and cerebral infarction ( ). Anaphylactic reaction following IVIg has been reported in patients with selective IgA deficiency due to IgG or IgE antibodies to IgA; IgA deficiency occurs in about 1 of every 200 to 800 persons. Thus, IgA deficiency is the only contraindication for the use of IVIg, and the IgA level should be checked when IVIg therapy is considered. If IVIg has to be given in an IgA-deficient patient, it should be infused with IVIg with low IgA levels (e.g., Gamimmune and Gammagard). An outbreak of hepatitis C was last reported with IVIg in early 1994. Death from acute renal failure in diabetic patients has been reported. Aseptic meningitis has become the most common troublesome side reaction to clinicians, seen in about 11% of patients. Most of other reactions are mild and self-limited and are associated with too rapid infusion of IVIg.

In a review of seven nonrandomized observational studies with 10 participants or more, Jongen et al. reported an overall rate of improvement of 76% (90/119), with a median of 87% (range, 48% to 92%) ( ; ). There were two randomized studies on IVIg versus placebo ( ; ). In one randomized controlled trial comparing IVIg (1 g/kg for 2 days) with placebo (5% dextrose for 2 days) in patients with MG worsening, there was a significant improvement in QMG in favor of the IVIg group on day 14 (class I) ( ). The treatment effect was maintained for 28 days after infusion in this study. Importantly, this effect was not observed in mild MG but was significant in moderate to severe MG. In another study comparing IVIg for 2 days versus 5% albumin for 3 days, there was not any significant difference in QMG change between the two groups ( ).

In a comparison of IVIg versus PE, four randomized controlled trials showed no difference in improvement between PE and IVIg ( ; ; ; ), suggesting that the efficacy of IVIg is as good as that of PE. Two randomized controlled trials compared the efficacy of two IVIg doses, 1 and 2 gm/kg, and found no difference in improvement between PE and IVIg and between the 1 and 2 gm/kg IVIg regimens.

IVIg was proposed as a maintenance therapy for MG. IVIg 2 gm/kg over 5 days was followed by 0.4 gm/kg once monthly or once every 6 weeks ( ; ; ). One study was conducted in 16 patients with severe GMG ( ), and another, in 11 patients with severe MG with bulbar palsy ( ). All patients were unresponsive to steroid and immunosuppresants. All patients improved after a mean period of 20 months. One study compared PE and IVIg as maintenance therapies for 27 juvenile MG patients and concluded that there is class III evidence that PE and IVIg both have high response rates as maintenance therapy ( ).

A Cochrane review concluded that IVIg is effective in severe MG exacerbation in one randomized controlled trial, but there is insufficient evidence from randomized trials to determine whether IVIg is efficacious in chronic MG ( ).

On the basis of these findings, we recommend IVIg to be used in lieu of PE for acutely worsening MG (class I) and preparation of weak patients for surgery including thymectomy (class IV) and to be used as an adjuvant to immunosuppressive therapy to minimize the long-term side effects of oral immunosuppressants and maintain an improved status of MG ( ). In MuSK-MG, a retrospective multicenter study on 52 patients showed a poorer outcome with IVIg compared with PE (class IV) ( ).

Eculizumab

Complement has been known to play an important role in the pathogenesis of MG, leading to the hypothesis that complement inhibition may lead to clinical improvement in MG ( ). Eculizumab, a complement inhibitor, is a C5 monoclonal antibody that inhibits the formation of C5b-9 membrane attack complex. Eculizumab is the first approved drug for MG by the FDA for treatment for adult patients with AChR-positive GMG after successful trials in 14 patients with severe refractory GMG (class I in Table 19.5 ) ( ). Six of seven (86%) patients treated with eculizumab for 16 weeks achieved the primary endpoint of a 3-point reduction in the QMG score ( P = 0.014 compared with placebo). In a subsequent phase 3 study in 125 patients, 62 receiving eculizumab and 63 receiving placebo for 26 weeks, the change in the QMG score showed a benefit with eculizumab compared with placebo ( P = 0.02) at week 26, but not in MG-ADL (activity of daily living) score. Most of the treatment effects occurred by week 12 and were sustained to week 26. The most common side reactions were headache and upper respiratory infection ( ). Thus, this drug is recommended for patients with moderate/severe GMG who are refractory to adequate trials with existing immunotherapy. The drug is given via IV infusion with a recommended dosage regimen of 900 mg/week for the first 4 weeks, 1200 mg for the fifth week, and 1200 mg every 2 weeks thereafter. Meningococcal vaccinations should be given 2 weeks before starting the first therapy to prevent any possible meningococcal infection.

Zilucoplan

Zilucoplan is another complement inhibitor that binds to C5b with high affinity and specificity, thus preventing the cleavage of C5 into C5a and C5b complement component and also blocking binding of C5b to C6 complement component. Unlike eculizumab, this agent is administered subcutaneously by the patient daily. A phase 2 randomized, double-blind, placebo-controlled multicenter trial was conducted in 44 AChR-Ab-positive Myasthenia Gravis Foundation of America (MGFA) II–IV GMG patients using three treatment groups (placebo, 0.3 mg/kg SC, and 0.1 mg/kg SC) over a 12-week period ( ). All participants were vaccinated against Neisseria meningitidis . Clinically meaningful and statistically significant improvements ( P < 0.05) in primary and key secondary efficacy end points were achieved in primary (QMG and MG-ADL scores) and secondary (MG Composite and MG Quality of Life Score) end points in the 0.3-mg/kg SC treated group compared with the placebo group. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but were slower in onset and less pronounced than with the 0.3-mg/kg dose. The onset of action was rapid, with separation of the 0.3-mg/kg arm from the placebo arm beginning after 1 week. Twenty-eight percent of participants did not experience an improvement as per the minimal clinically important difference of 3 points on the QMG score. The drug was well tolerated, with mild adverse events and a low incidence of local injection site reaction. Zilucoplan may have an advantage over ecluzumab in view of the easy subcutaneous injection route. As of March 1, 2020, this drug has not been approved for MG by the FDA.

Rituximab

Rituximab is a chimeric mouse/human anti-CD20 monoclonal immunoglobulin. According to a 2017 review, 169 MG (59% AChR-Ab positive; 34% MuSK-Ab positive) patients were treated with rituximab ( ). Rituximab treatment achieved minimal manifestation (LMm) or better status, according to the modified MGFA postintervention scale, in 44% of treated patients and combined pharmacologic and chronic stable status in 27%. MM or better status was achieved in 72% of MuSK MG and 30% of AChR MG patients ( P <0.001). Response predictors were MuSK MG, less severe disease, and younger age at treatment. A multicenter blinded review study showed that patients treated with rituximab met the end goal of an MG Status and Treatment Intensity score of 2 higher, which was statistically significant compared with the control group: 58% (14/24) of rituximab-treated patients versus 16% (5/21) of control patients (class IV) ( ). These two studies suggest that rituximab may be more effective in MuSK MG. However, this drug needs to be evaluated more extensively against the current immunosuppressants before it can be recommended. Common infusion-related side effects of rituximab are fever, chills, nausea, vomiting, flushing, and bronchospasm. Other, more serious side effects include neutropenia and increased risk of infection.

Thymectomy

In 1939, Blalock et al. reported the remission of GMG in a 21-year-old woman after removal of a cystic thymic tumor and subsequently performed thymectomy on MG patients without thymoma, found hyperplasia in the thymus glands, and reported improvement in at least half of their patients ( ). Since this report, thymectomy has been accepted widely as a standard form of treatment for MG on the basis of class II evidence ( ). In 2016, the first randomized trial comparing thymectomy with medical management in nonthymomatous patients was published ( ). A total of 126 recently diagnosed patients, ages 18 through 65 years, with AChR antibody-positive GMG with duration of 3 to 5 years were randomized to receive either extended transsternal thymectomy plus prednisone versus medical management with prednisone. Over a 3-year follow-up period, the time-weighted average QMG score was lower in the patients who underwent thymectomy (6.15 vs. 8.99; P < 0.001), and alternate-day prednisone dose requirement was lower (32 vs. 54 mg; P < 0.001). In the thymectomy group, fewer patients required immunosuppression with AZA or were hospitalized for exacerbation ( P < 0.001). The effects of thymectomy began to be observed as early as 3 to 4 months but became definite at 9–12 months and were maintained for the entire 3-year study. The results of this study provides class I evidence for thymectomy in all generalized AChR-positive patients to improve MG status and decrease the required dose of immunotherapy in GMG. A recent analysis on 50 patients (24 prednisone alone and 26 prednisone and thymectomy) showed that at 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalized nonthymomatous GMG compared with prednisone alone ( ). Current evidence does not support an indication for thymectomy in patients with MuSK, LRP4, and agrin antibodies ( ; ).

At this time, the indication for thymectomy in AChR-negative GMG patients is controversial. Two retrospective cohort studies showed comparable responses among AChR-positive and AChR-negative groups ( ; ; ).

Age is another controversial subject in thymectomy ( ; ). Thymectomy is often avoided in children because of the theoretical possibility of impairing the developing immune system. However, reports of thymectomy in children as young as 2 to 3 years of age have shown favorable results, without adverse effects on the immune system ( ). Thymectomy has been largely discouraged in late-onset MG (>65 years of age) mainly because of frequent observations of an atrophic, involuted thymus. One series showed a less favorable outcome of thymectomy in late-onset MG: postthymectomy improvement was transitory and no longer detectable at 2 years after thymectomy (class IV) ( ). The age at MG onset is a more important factor than the age at thymectomy( ). Considering the benefit of thymectomy up to 65 years of age in the randomized study, it is reasonable to extend thymectomy age to 65 years ( ).

A randomized thymectomy trial mandated an extended transdermal thymectomy ( ). Less invasive procedures are now available for thymectomy: transcervical, video-assisted thoracoscopic surgery (VATET), and robotic video-assisted thoracoscopic surgery. VATET offers shorter hospital duration and stay and limited morbidity.

In comparing the various surgical approaches, employed Kaplan-Meier life table analysis at 5 years and concluded that the combined transcervical-transsternal, extended transsternal, extended cervical, and VATET procedures appear to produce more or less the same percentage (40%–55%) of remission at 5 years. It appears that the more thorough the removal of all tissue that may contain thymus, the better the longer-term results. Therefore, conceptually, the combined transcervical-transsternal thymectomy best fulfills these criteria.

Sonett and Jaretzki also stated that it is far preferable to leave behind small amounts of suspected thymus, or even likely thymus, than injuring the recurrent laryngeal, the left vagus, or the phrenic nerve. Injuries to these nerves can be devastating to a patient with MG ( ).

On the basis of this information, we believe that thymectomy is indicated in any early-onset (<65 years of age) GMG patients whose symptoms are not satisfactorily controlled with AChEIs alone and initial immunotherapy (class I recommendation for AChR-Ab-positive patients and level B recommendation for AChR-Ab-negative patients. We take this view on the basis of the findings that AChR antibodies were found in 66% of seronegative sera by a clustered AChR cell–based assay) ( ; , on the other hand, listed thymectomy as the first-line treatment of MG in their recommendation. Thymectomy induces long-term improvement and remission. About 33% of patients will achieve remission in the first 3 years after thymectomy, and 50% within 5 years ( ). Thymectomy produces a stable remission by eliminating thymic centers. The effects are delayed because of the long life-span of the existing pool of small immunocompetent lymphocytes.