Clinical characteristics and outcome of treatment-refractory myasthenia gravis -a retrospective study

doi:10.21203/rs.3.rs-4378704/v1

Download PDF

Research Article

Clinical characteristics and outcome of treatment-refractory myasthenia gravis -a retrospective study

https://doi.org/10.21203/rs.3.rs-4378704/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Objective

This study aimed to investigate the frequency, clinical characteristics, and outcomes of treatment-refractory myasthenia gravis (MG) in a Chinese cohort.

Methods

A retrospective cohort of 277 MG patients was conducted between August 2016 and May 2023. Patients were classified as refractory if their Myasthenia Gravis Foundation of America post-intervention status (MGFA-PIS) was categorized as “unchanged” or “worse”. Additionally, patients with persistent symptoms and functional limitations despite at least 12 months of concurrent immunosuppressive therapy, including adequately dosed steroids and two other immunosuppressive drugs, were also classified as refractory. The clinical features and outcomes at the end of follow-up of drug-refractory patients were compared with those of drug-responsive patients.

Results

Of the 277 patients, 36 were unequivocally diagnosed with refractory MG. Treatment-refractory patients frequently presented at a younger age, with a generalized form of the disease, and with bulbar/or respiratory symptoms at onset. These patients also exhibited higher disease severity than non-drug-refractory patients. Furthermore, patients classified as drug-resistant experienced a longer interval between disease onset and the initiation of immunotherapy. At the end of follow-up, poor outcome was more frequently found in treatment-refractory MG patients.

Conclusion

This study found that 13% of MG patients were classified as drug-refractory. There is a need for new, more specific drugs to treat drug-refractory MG patients.

refractory myasthenia gravis

operative definition of refractory myasthenia gravis

clinical characteristics

outcomes

MG is a rare autoimmune disorder that affects the neuromuscular junction, characterized by fluctuating muscle weakness involving ocular, skeletal, or bulbar muscles. The global prevalence of MG is reported to be between 100 and 200 cases per million individuals[1], with an annual incidence ranging from 4 to 12 cases per million[2]. The observed increase in prevalence and incidence rates can be partially attributed to more extensive autoantibody testing, the extended lifespan of the general population, and advancements in disease management leading to reduced mortality in MG patients. Approximately 85% of MG patients exhibit antibodies against the muscle acetylcholine receptor (AChR)[3]. In contrast, 1–10% of patients are found to have antibodies against muscle-specific kinase (MuSK)[4]. Notably, around 15% of patients demonstrate double-seronegative status when tested for both anti-AChR and anti-MuSK antibodies using standard diagnostic methods[5].

The prognosis for the majority of patients with MG has markedly improved, primarily due to the increased utilization of acetylcholinesterase inhibitors, glucocorticosteroids, and conventional immunosuppressants. This improvement is also attributed to thymectomy and rescue interventions for myasthenic crises in certain cases. However, a subset of MG patients remains refractory to treatment. Previous literature reports that this group constitutes approximately 10 to 20% of cases[6–9]. These patients often experience severe fatigue, significant disability, substantial side effects, and elevated costs associated with ongoing traditional immunosuppressant therapy and recurrent myasthenic crises, which frequently result in hospitalizations.

Despite the release of an international consensus on the definition of refractory MG in 2016[10], which has yet to be widely applied, the literature still presents several differing definitions[11, 12] This diversity in definitions accounts for the variability in the characteristics of treatment-resistant patients across studies, posing challenges for cross-study comparisons. Practically speaking, the timely and accurate identification of refractoriness in MG patients is imperative, as this subset may benefit from specifically escalated treatment regimens. Conversely, escalating treatment in patients who are not genuinely refractory could lead to greater risks than potential benefits. Considering the unmet clinical needs in the management of treatment-refractory MG, establishing a universally accepted definition and further characterizing this subgroup are essential. This will facilitate the early recognition and selection of patients for targeted management with novel biological agents.

The objective of this study was to delineate the clinical and therapeutic characteristics, as well as the outcomes, of patients with refractory MG, defined stringently, and to compare these attributes with those of patients who were non-drug-refractory.

This study was a single-center, retrospective cohort study which aims to explore the clinical characteristics and clinical outcome of refractory MG meeting ICG criteria in Chinese population.

2.1 Patients

Patients diagnosed with MG, who presented at Xiangya Hospital in Hunan province, China, between August 1, 2016, and June 30, 2021, were consecutively included. The diagnosis of MG was based on the presence of characteristic myasthenic symptoms, primarily fluctuating muscle weakness exacerbated by fatigue, and confirmed by the detection of MG-associated antibodies. Patients who did not exhibit serum antibodies against AChR and MuSK were classified as double-seronegative MG. Their diagnosis was corroborated through pathological repetitive nerve stimulation exhibiting a decrement of over 10%, a positive neostigmine test, or clinical improvement following pyridostigmine treatment.

This study included only patients with a minimum follow-up period of 24 months post-diagnosis of MG to ensure sufficient data for determining their classification as refractory MG patients or otherwise. The exclusion criteria were as follows: (1) patients under the age of 15 years; (2) patients with less than 24 months of follow-up; (3) patients with inconsistent intake of immunosuppressive medication during the follow-up period; and (4) patients with incomplete records or who were unable to provide treatment information, or those who declined immunotherapy.

2.2 Data collection

Data on the demographic, clinical, immunological, and therapeutic characteristics of MG patients were gathered from medical records and telephone follow-ups. The Myasthenia Gravis Foundation of America (MGFA) class and quantitative scores at the initial visit, disease peak, and last follow-up were determined by a specialized technician at Xiangya Hospital. Serum levels of anti-AChR, anti-Titin, and anti-RyR antibodies were measured by the Guangzhou Daan Clinical Laboratory Center. This center employed enzyme-linked immunosorbent assay for anti-AChR, anti-Titin, and anti-RyR antibodies, and radioimmunoassay for anti-MuSK antibody detection (RiaRSR™, United Kingdom), and was blinded to the patients' clinical conditions. MG patients were categorized into six subgroups based on a previous literature review[8]. The QMGs, MGFA class and MG-ADL was assessed by specialized physicians. Data on the number of myasthenic and impending crises, rescue treatments administered, and the duration from onset to last follow-up were also compiled.

2.3 Diagnosis of refractory MG

Patients with refractory MG were identified based on the criteria set forth in the International Consensus Guidance (ICG)[10]. According to these criteria, refractory MG is characterized by a static or deteriorating MGFA-PIS, despite the administration of corticosteroids and at least two other immunosuppressive agents in appropriate doses for a sufficient period. Additionally, these patients exhibited persistent symptoms or side effects that limited their functional capabilities.

While an inadequate therapeutic response or the occurrence of side effects in MG patients may stem from various pathogenic mechanisms, this study focused on patients demonstrating a suboptimal response to treatment. Consequently, the study utilized the ICG criteria, elaborated in detail by C. Tran et al[12], which specifically exclude cases primarily associated with side effects.

(1) The status of "unchanged" and "worse" in the MGFA-PIS [13] was determined based on changes in QMGs (details in latter section).

(2) Ongoing symptoms were identified through the absence of a patient-acceptable symptom status (PASS) [14]. QMG scores exceeding 7 or Myasthenia Gravis Activities of Daily Living (MG-ADL) scores above 2, which did not meet the PASS criteria, were considered as indicative of clinically significant persistent symptoms.

(3) The requirement for an ‘adequate dose over an adequate duration’ was defined as the consistent administration of corticosteroids (20-60mg daily) and at least two other immunosuppressants for a minimum of 12 months. The specific doses for azathioprine were 100-300mg daily, and for mycophenolate mofetil, 2-3g daily. Tacrolimus dosages were tailored based on serum titers, as its use is concentration-directed. The established optimal serum concentration for therapeutic effect in MG was identified as above 4.8 ng/mL[15].

2.4 Outcomes

Outcomes were evaluated based on the MGFA-PIS at the final visit. Outcomes were categorized into ‘minimal manifestation (MM) or better status’, ‘Improved’, ‘Unchanged’, ‘Worse’, and ‘Death’, as adapted from the MGFA-PIS classification[13]. The ‘MM or better’ status, as per the ICG recommendation[10], is defined as a state where the patient exhibits no symptoms or functional limitations from MG, but some muscle weakness is observable upon examination. The MGFA-PIS status was defined as follows: (1) for baseline QMGs > 16, ‘Improved’ indicated a reduction in score by 3 or more, ‘Unchanged’ indicated an increase or decrease in score by less than 3, and ‘Worse’ indicated an increase in score by 3 or more; (2) for baseline QMGs ≤ 16, ‘Improved’ indicated a reduction in score by 2 or more, ‘Unchanged’ indicated an increase or decrease in score by less than 2, and ‘Worse’ indicated an increase in score by 2 or more. “Died” indicated the patient died of MG. The “Unchanged” “Worse” and “Died” were classified as poor outcome.

2.5 Statistical analysis

Comparisons between drug-refractory and drug-responsive MG patients regarding clinical characteristics and outcomes were performed using the t-test or the Mann-Whitney U test for continuous variables, and the Chi-squared test for categorical variables. Statistical analyses were conducted using SPSS software, version 26.0 (IBM Corp., Armonk, New York). A p-value of < 0.05 was considered statistically significant.

Logistic regression model was carried out to adjust potential confounders for primary outcome and to identify independent risk factors among baseline variables that might correlate with the occurrence of refractory MG. Candidate variables with a p value < 0.15 on univariate analysis or considered clinically relevant were included in the multivariable model. These confounders were baseline imbalanced variables or different therapeutic strategies. A p-value of < 0.05 in the multivariate logistic analysis was deemed statistically significant.

3.1 patients’ baseline characteristics

A total of 540 patients diagnosed with MG were identified from the records of Xiangya Hospital, Hunan province, China, between August 2016 and May 2023. Exclusions were made for 20 patients lacking relevant clinical data, 2 with double-positive antibodies, 113 with ambiguous classification, and 82 due to insufficient follow-up. Consequently, 277 MG patients were eligible for evaluation, consisting of 100 males (36.1%) and 177 females (63.9%). Among these, 36 (13%) were classified as treatment-refractory, while 241 (87%) were categorized as treatment-responsive, as depicted in Fig. 1.

Baseline variables for patients in the treatment-refractory group and the treatment-responsive group are detailed in Table 1. No significant differences were observed between the two groups in terms of gender, age at onset, antibody status, presence of thymoma, thymectomy status, and major comorbidities. However, patients in the refractory group were more frequently diagnosed with generalized MG (97.2% vs. 77.6%, p = 0.005) and exhibited bulbar and/or respiratory weakness more commonly at disease onset (52.8% vs. 34%, p = 0.029) compared to the responsive group. Notably, patients with drug resistance were more often categorized as early-onset myasthenia gravis (EOMG) with positive AChR antibody compared to late-onset MG (LOMG) (p = 0.045). Additionally, the time from onset to immunosuppressive treatment initiation was longer in refractory patients compared to those responsive to immunosuppressants (median 16, quartile 4.3–64.3 vs. median 6, quartile 1.1–27, p = 0.012). Drug-refractory patients also exhibited higher disease severity at onset, indicated by higher Quantitative Myasthenia Gravis scores (median 17, quartile 10.25-20 vs. median 10, quartile 7–16, p < 0.001) and a higher proportion of moderate to severe MGFA class (MGFA class III to V: 86.1% vs. 45.2%, p < 0.001).

Table 1

Characteristics of treatment-refractory MG and treatment-response MG.
Group	Treatment-refractory MG (n = 36)	Treatment-responsive MG (n = 241)	P value
Gender			> 0.999
Male	13(36.1%)	87(36.1%)
Female	23(63.9%)	154(63.9%)
Onset-age (years, mean ± SD)	41.0 ± 15.4	39.1 ± 13.7	0.490
Antibody			0.235
AChR Ab	34(94.4%)	203(84.2%)
MuSK Ab	0(0%)	9(3.7%)
Double-seronegative	2(5.6%)	29(12.1%)
Titin Ab	5(13.9%)	31(12.9%)	0.794
RyR Ab	2(5.6%)	22(9.1%)	0.751
OMG	1(2.8%)	51(22.4%)	0.005^*
GMG	35(97.2%)	190(77.6%)	0.005^*
Bulbar/respiratory involvement at onset	19(52.8%)	82(34.0%)	0.029^*
MGFA classification at onset			< 0.001^*
Ⅰ	2(5.6%)	57(22.4%)
Ⅱ	3(8.3%)	75(31.1%)
Ⅲ	17(47.2%)	62(25.7%)
Ⅳ	14(38.9%)	44(18.3%)
Ⅴ	0(0%)	3(1.2%)
Baseline QMGs (median, quarters)	17(10.25-20)	10(7–16)	< 0.001^*
Thymoma	8(22.2%)	50(20.8%)	0.2319
Subtype			0.045^*
OMG	1(2.8%)	49(20.3%)
EOMG with AChR Ab	19(52.8%)	74(30.7%)
LOMG with AChR Ab	6(16.7%)	43(17.8%)
TAMG	8(22.2%)	50(20.8%)
MuSK-associated MG	0(0%)	9(3.7%)
Seronegative GMG	2(5.6%)	16(6.6%)
comorbidity^†	7(19.4%)	43(17.8%)	0.816
Median time from onset to IST (months, median, quarters)	16(4.3–64.3)	6(1.1–27)	0.012^*
AChR Ab, acetylcholine receptor antibody; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; MuSK, muscle-specific tyrosine kinase; RyR, ryanodine receptor; EOMG; early-onset myasthenia gravis;LOMG; late-onset myasthenia gravis; IST, immunosuppressive treatment; GMG, generalized myasthenia gravis; TAMG, thymoma-associated myasthenia gravis. ^†: comorbidity including systemic lupus erythematosus, leukoderma, pemphigus, allergic rhinitis, dermatomyositis, atopic dermatitis, Graves’ disease and autoimmune thyroid disease. *: statistically significant.

The variables included in the multivariate logistic analysis for the diagnosis of refractory MG were shown in Table 2. The univariate analysis demonstrated that duration from onset to IST, OMG, involvement of bulbar or respiratory muscle and baseline disease severity were correlated with developing treatment-refractory MG. In further multivariate regression analysis, following variates were found to be independent risk factors for refractory MG: early onset (OR = 2.991, 95%CI 1.093–8.182, p = 0.033), longer duration(> 12 months) from onset to IST(OR = 2.469, 95%CI 1.214–5.020, p = 0.0013) and baseline disease severity classified as moderated to severe (OR = 7.623, 95%CI 2.141–27.137, p = 0.002). While, OMG or bulbar/respiratory muscle involved, shown no significant relationship with refractory MG in multivariate analysis.

Table 2

Involved factors may be associated with diagnosing treatment-refractory MG
	Univariate survival analysis, HR (95%CI)	p	Multivariate survival analysis, HR (95%CI)	p
Onset-age
<50 years VS ≥ 50 years	0.534(0.233–1.224)	0.138	2.514(1.014–62.234)	0.047^*
Gender
Female VS male	1.000(0.482–2.072)	> 0.999	-	-
Duration from onset to IST
> 12 months VS ≤ 12 months	2.469(1.214–5.020)	0.013^*	2.278(1.055–4.921)	0.036^*
Antibody status ^†
MuSK-Ab VS AChR-Ab	0	> 0.999	0	> 0.999
Double negative VS AChR-Ab	0.412(0.094–1.806)	0.412	0.631(0.110–3.614)	0.605
Titin-Ab and RyR-Ab^‡
Titin-Ab positive VS negtive	2.289(0.693–7.559)	0.174	-	-
RyR-Ab pisitive VS negtive	1.144(0.133–9.838)	0.902	-	-
Both positive VS negtive	0.404(0.052–3.147)	0.387	-	-
Purely ocular involvement
GMG VS OMG	9.162(1.225–68.518)	0.031^*	2.939(0.329–26.275)	0.335
Bulbar/respiratory muscle involved
Involved VS uninvolved	2.167(1.069–4.393)	0.032^*	0.575(0.233–1.419)	0.230
Baseline disease severity
Medium-severe VS mild	7.384(2.777–16.634)	< 0.001^*	5.645(1.742–18.291)	0.004^*
Comorbidity
With VS without	1.111(0.457–2.703)	0.816	-	-
Thymoma
With thymoma VS without thymoma	1.111(0.457–2.703)	0.816	1.548(0.557–4.297)	0.402
VS: versus; AChR-Ab: acetylcholine receptor antibody; MuSK-Ab: muscle-specific tyrosine-protein kinase receptor antibody; MG: myasthenia gravis; OMG: ocular myasthenia gravis; GMG: generalized myasthenia gravis; IST: immunosuppressor treatment; GCs: glucocorticoids; TAC: tacrolimus; MMF: mycophenolate mofetil
^†: the adjusted significance level α = 0.025, ^‡: the adjusted significance level α = 0.0167

3.2 Treatment and outcomes

Table 3 presents the worst severity, treatments, and outcome measures. Patients categorized as treatment-refractory displayed significantly higher QMGs at peak disease exacerbation (median 20, quartile 17.3–24.5) compared to the treatment-responsive group (median 12, quartile 8–17, p < 0.001). Furthermore, a more severe Myasthenia Gravis Foundation of America classification (MGFA class III to V) was observed in 97.2% of refractory patients, versus 53.5% in responsive patients (p < 0.001), as depicted in Fig. 2. These quantitative findings corroborate previous research outcomes[6, 14, 15].

Table 3

Worst severity and outcome in treatment-responsive and treatment-refractory MG
Group	Treatment refractory MG (n = 36)	Treatment responsive MG (n = 241)	P value
Max MGFA class			< 0.001^*
Ⅰ	1(2.8%)	52(21.6%)
Ⅱ	0(0%)	60(24.9%)
Ⅲ	13(36.1%)	73(30.3%)
Ⅳ	17(47.2%)	52(21.6%)
Ⅴ	5(13.9%)	4(1.7%)
Max QMGs (median, quarters)	20(17.3–24.5)	12(8.0–17.0)	< 0.001^*
Thymectomy	8(22.2%)	54(22.4%)	0.980
Immunosuppressive treatment
GCs	36(100%)	159(66.0%)	< 0.001^*
TAC	33(91.7%)	168(69.7%)	0.011^*
MMF	28(77.8%)	82(34.0%)	< 0.001^*
AZA	6(16.7%)	38(15.8%)	0.915
CTX	1(2.8%)	0(0%)	0.130
MTX	1(2.8%)	0(0%)	0.130
Leflunomide	1(2.8%)	1(0.4%)	0.6124
Ofatumumab	0	4(1.7%)	> 0.999
Myasthenic crisis/impending crisis	18(50%)	54(22.4%)	0.001^*
Rescue treatment ^†	20(55.6%)	53(22.0%)	< 0.001^*
MGFA class at last FU			< 0.001^*
Asymptomatic	0(0%)	111(46.1%)
Ⅰ	3(8.3%)	27(11.2%)
Ⅱ	12(33.3%)	73(30.3%)
Ⅲ	14(38.9%)	22(9.1%)
Ⅳ	6(16.7%)	8(3.3%)
Ⅴ	1(2.8%)	0(0%)
QMGs at last FU	13.5(8.3–17.8)	4.0(2.0–6.0)	< 0.001^*
MGFA-PIS at last FU			< 0.001^*
MMS or better	0(0%)	111(46.1%)
Improved	21(58.3%)	101(41.9%)
Unchanged	8(22.2%)	16(6.7%)
Worse	6(16.7%)	13(5.4%)
Died of MG	1(2.8%)	0(0%)
Median time onset to FU (months, median, quarters)	34.5(28.5–49.8)	34(25.0-46.5)	0.350
MGFA, Myasthenia Gravis Foundation of America; QMGs, quantitative myasthenia gravis scores; GCs, glucocorticoids; TAC, tacrolimus; MMF, mycophenolate mofetil; AZA, azathioprine; CTX, Cyclophosphamide; FU follow-up, PIS postintervention status, MMS Minimal manifestation status. ^†: Rescue treatment including intravenous immunoglobulins (IVIG), plasma exchange therapy (PLEX) and intravenous high-dose methylprednisolone (IVMP). *: Significantly different.

In both drug-refractory and non-drug-refractory cohorts, a substantial administration rate of first-line glucocorticoids was observed (100% vs. 66%, p < 0.001). Refractory patients were more likely to receive second-line therapies such as tacrolimus and mycophenolate mofetil (91.7% vs. 69.7%, p = 0.011; 77.8% vs. 34%, p < 0.001, respectively). The incidence of myasthenic crisis or impending crisis, as well as the need for rescue treatment during the disease course, was notably higher in the treatment-refractory group compared to the treatment-responsive group (50% vs. 22.4%, p = 0.001; 55.6% vs. 22%, p < 0.001, respectively).

At the last follow-up, after a median duration of 34.5 months for the treatment-resistant group and 34 months for the treatment-responsive group (p = 0.350), those meeting the criteria for treatment-refractory MG exhibited higher QMGs and MGFA classes at the last visit than responsive patients, as shown in Fig. 2. Additionally, regarding the MGFA-PIS at the last follow-up, drug-resistant patients demonstrated a higher proportion of “Unchanged” and “Worse” status, along with one patient in “Died of MG” status, compared to those who responded to treatment (41.7% vs. 12.2%, p < 0.001, respectively). Treatment-refractory MG exhibited higher proportion of poor outcome, compared to the treatment-responsive group (41.7% VS 12.0%). Univariate logistic regression demonstrated treatment-refractory was associated with the poor outcome (OR = 5.222,95% CI 2.423–11.253, p < 0.001). After adjusted the potential confounders, including the onset-age, antibody status, thymoma, duration from onset to IST, muscles group involved and therapeutic drugs, the treatment-refractory MG was still proved to be risk factor for poor outcome (OR = 13.879. 95%CI 4.451–43.275, p < 0.001) ,as shown in Table 4.

Table 4

Involved factors may be associated with poor outcome
	Univariate survival analysis, OR (95%CI)	p	Multivariate survival analysis, OR (95%CI)	p
Treatment response
Refractory VS responsive	5.222(2.423–11.253)	< 0.001^*	13.879(4.451–43.275)	< 0.001^*
Onset-age
<50 years VS ≥ 50 years	1.599(0.768–3.330)	0.210	1.251(0.557–2.811)	0.587
Time from onset to IST
> 12 months VS ≤ 12 months	0.783(0.394–1.558)	0.486	0.601(0.278–1.301)	0.196
Antibody status^‡
MuSK-Ab VS AChR-Ab	2.703(0.647–11.289)	0.173	9.265(1.669–51.438)	0.011^*
Double negative V.S AChR-Ab	0.801(0.265–2.423)	0.694	0.636(0.194–2.086)	0.455
Skeleton muscle symptoms
GMG VS OMG	0.726(0.332–1.586)	0.422	0.796(0.288–2.201)	0.659
Bulbar/respiratory muscle involved
with VS without	0.783(0.394–1.558)	0.486	0.715(0.275–1.861)	0.492
Peak disease severity^†
Moderate-severe VS mild	0.890(0.464–1.707)	0.725	0.553(0.174–1.758)	0.316
Thymoma
with VS without	1.204(0.538–2.697)	0.652	1.188(0.489–2.883)	0.704
GCs
No exposure VS exposure	1.122(0.546–2.306)	0.754	0.654(0.253–1.688)	0.380
TAC
No exposure VS exposure	1.010(0.490–2.081)	0.979	0.626(0.250–1.568)	0.317
MMF
No exposure V.S exposure	1.324(0.692–2.535)	0.397	0.919(0.409–2.056)	0.839
Crisis/impending crisis
With VS without	1.106(0.535–2.286)	0.786	0.939(0.337–2.616)	0.903
VS, versus; IST, immunosuppressive treatment; AChR-Ab, acetylcholine receptor antibody; MuSK-Ab, muscle-specific tyrosine-protein kinase receptor antibody; RyR, ryanodine receptor; GMG, generalized myasthenia gravis; OMG, ocular myasthenia gravis; GCs, glucocorticoids; TAC, tacrolimus; MMF, mycophenolate mofetil. ^†: disease severity was classified into mild myasthenic symptoms (i.e., MGFA class I to II) and moderate to severe myasthenic symptoms (i.e., ≥ MGFA class III). ^‡ The adjusted significance level α=0.025 ^*: significantly different.

In this retrospective study, we examined the frequency, clinical characteristics, and outcomes of treatment-resistant MG patients within a Chinese cohort. Despite the availability of multiple therapeutic options, 13% of patients exhibited treatment refractoriness. These individuals were more likely to have an early onset age, display more severe disease severity initially, experience more life-threatening events, and require more rescue treatments compared to their non-drug-refractory counterparts. Furthermore, it was observed that patients who developed drug refractoriness during the course of their illness continued to have worse outcomes, despite concurrent immunosuppressive therapy.

Our study found that the frequency of refractory patients aligns with previous research, where approximately 10–20% of patients were identified as treatment-resistant[7, 9, 14, 16]. Variations in the frequency of refractoriness may be attributed to the evolving definitions of drug-refractoriness over time. Significantly, our study employed a stringent definition of treatment-refractory MG, based on quantitative scores for clinical symptom assessment[10, 12], which diverges somewhat from criteria suggested in earlier studies. The criteria we adopted, a complementary perspective to ICG criteria, was a more practical operability assessment system.

A significant observation from our study is that drug-refractory MG patients did not exhibit a distinct antibody profile, aligning with findings from Rath et al. And the MuSK-Ab positive may be risk factor of poor outcome (displayed in Table 4). Some previous studies have indicated a less favorable response in refractory MG patients with seronegative antibodies[17], contrasting with reports of less disease severity in seronegative than seropositive patients[18], the majority of previous research has identified a higher prevalence of MuSK antibody positivity in refractory cases[1, 6, 7, 9, 12, 19]. The heterogeneity in the antibody profile of refractory patients may be attributed to varying criteria, which tend to be more lenient in single-center studies in previous research. Additionally, the non-significance of antibody subgroups in this study could be due to the low prevalence of anti-MuSK antibody-positive MG in mainland China[20], coupled with effective early treatment and improved management of anti-MuSK antibody-positive MG, leading to better outcomes.

In our study, patients with disease onset before the age of 50 years demonstrated a higher likelihood of developing treatment-refractory MG compared to those diagnosed after 50, aligning with findings from previous studies[7, 14]. This trend could be explained by increased activation of the immune system, particularly T lymphocytes, in younger patients, which influences the response to immunosuppressants. Additionally, our analysis revealed no significant difference in the proportion of female patients or the presence of thymoma between the treatment-resistant and treatment-responsive groups, contrasting with findings from some earlier studies[6, 11]. This discrepancy could be due to several factors. Firstly, the non-difference in MuSK-antibody prevalence, which exhibits a strong female predominance[21], might account for the parity in female representation between the two groups in our study. Furthermore, the lack of a significant association between thymoma and refractory MG in our research could be attributed to the proactive management strategy at our center, where the majority of thymomatous MG patients undergo early thymectomy. Although patients with thymoma-associated MG often present with more severe clinical symptoms and a tendency towards treatment resistance[22], the direct impact of thymoma resection on refractory MG status remains unclear due to insufficient definitive evidence.

Our study found that the time from disease onset to the initiation of immunosuppressive treatment significantly varied between the two groups, contrasting with findings from Rath et al[1], yet indirectly supported by evidence that a shorter time to diagnosis correlates with better outcomes. This suggests that delayed therapy may be risk factor for refractory MG and patients might benefit from more rapid treatment intervention. Additionally, we noted that drug-refractory patients exhibited higher disease severity and poorer outcomes at the last follow-up, even adjusted the imbalanced baseline and immunosuppressive treatment regimens. Interestingly, while previous research indicated that about 10% of refractory MG patients achieved minimal manifestation status (MMS) or remission according to MGFA-PIS criteria[6], and a few cases reached a mild MGFA class or even became asymptomatic after at least 24-month follow-ups[14], none of the drug-resistant patients in our study reached MMS by the end of follow-up, with one patient succumbing to myasthenia-related symptoms. These findings underscore the necessity for a clear and functional definition of refractoriness in MG. Contrary to expectations, differences in the incidence of impending crises and myasthenic crises, as well as the subsequent need for more rescue treatments reflecting disease severity during its course, were not observed in our study.

This study is subject to certain inherent limitations that merit consideration. Firstly, the retrospective design of the study may introduce potential investigator bias, which could influence the outcomes. Secondly, given its single-center nature and the relative rarity of the refractory subgroup, the study enrolled limited cases, the results need to be verified by further multiple centre study. Additionally, there is a possibility that the percentage of patients experiencing treatment failure might be overestimated in this study. This could be attributed to the likelihood of excluding patients who achieved successful therapy outcomes before completing 24 months of follow-up, owing to the study's restrictive follow-up duration criteria.

Our study delineated the frequency and clinical characteristics of treatment-resistant MG in mainland China, despite patients receiving adequate doses of corticosteroids and at least two concurrent immunosuppressive drugs for a minimum of one year. A key strength of this study lies in addressing the ambiguity surrounding the assessment of clinical symptoms in the ICG criteria by incorporating findings from various original researches[23–26]. Our approach focused on utilizing operational assessment of clinical symptoms, in contrast to previous definitions of refractory MG.

This study found that 13% of MG patients were classified as drug-refractory MG and they had higher risk to present poor prognosis. There is a need for new, more specific drugs to treat drug-refractory MG patients.

myasthenia gravis

AChR

acetylcholine receptor

MuSK

muscle-specific tyrosine kinase

ICG

International Consensus Guidance

MGFA-PIS

Myasthenia Gravis Foundation of America post-intervention

minimal manifestation

QMGs

quantitative myasthenia gravis scores

MG-ADLs

MG activities of daily living scores

RyR

ryanodine receptor

IST

immunosuppressive treatment

EOMG

early-onset myasthenia gravis

LOMG

late-onset myasthenia gravis

TAMG

thymoma-associated myasthenia gravis

IVIG

intravenous immunoglobulin

PLEX

plasma exchange

PASS

patient-acceptable symptom status.

Supplementary information

Not applicable.

Ethics approval and consent to participate

The study complied with the Declaration of Helsinki. All participants were informed and signed the consent form for the study and was approved by the Medical Ethics Committee of the Hunan Medical Science Research Institute of Xiangya Hospital (202103207).

Consent for publication

All authors have approved the content and agreed to submit the article in consideration for publication.

Availability of data and materials

The dataset supporting the conclusions of this article is available in the Figshare repository. https://doi.org/10.6084/m9.figshare.25107599

Competing interest

The authors declare that there are no conflicts of interest.

Funding

Project founded by National Natural Science Foundation of China (grant number 82171399).

Authors contribution

Huan Yang: conception, study design, revision of the manuscript; Yi Li: manuscript writing, interpretation of the results and collection of data; Shumei Yang: data collection and manuscript revision; Xiaohua Dong, Fei Jiang, Kangzhi Chen, Qian Zhou, Haobin Cai participated in the collection of data.

Acknowledgement

We thank all the clinical staff who supported our study in Xiangya Hospital.

Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve. 2004;29(4):484–505.
Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. 2010;10:46.
Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology. 1976;26(11):1054–9.
Evoli A, Alboini PE, Damato V, Iorio R, Provenzano C, Bartoccioni E, Marino M. Myasthenia gravis with antibodies to MuSK: an update. Ann N Y Acad Sci. 2018;1412(1):82–9.
Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmun. 2014;48–49:143–8.
Cortés-Vicente E, Álvarez-Velasco R, Pla-Junca F, Rojas-Garcia R, Paradas C, Sevilla T, Casasnovas C, Gómez-Caravaca MT, Pardo J, Ramos-Fransi A, et al. Drug-refractory myasthenia gravis: Clinical characteristics, treatments, and outcome. Ann Clin Transl Neurol. 2022;9(2):122–31.
Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med. 2013;86(2):255–60.
Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14(10):1023–36.
Sudulagunta SR, Sepehrar M, Sodalagunta MB, Settikere Nataraju A, Bangalore Raja SK, Sathyanarayana D, Gummadi S, Burra HK. Refractory myasthenia gravis - clinical profile, comorbidities and response to rituximab. Ger Med Sci. 2016;14:Doc12.
Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, Kuntz N, Massey JM, Melms A, Murai H, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016;87(4):419–25.
Mantegazza R, Antozzi C. When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies. Ther Adv Neurol Disord. 2018;11:1756285617749134.
Tran C, Biswas A, Mendoza M, Katzberg H, Bril V, Barnett C. Performance of different criteria for refractory myasthenia gravis. Eur J Neurol. 2021;28(4):1375–84.
Narayanaswami P, Sanders DB, Wolfe G, Benatar M, Cea G, Evoli A, Gilhus NE, Illa I, Kuntz NL, Massey J, et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. 2021;96(3):114–22.
Rath J, Brunner I, Tomschik M, Zulehner G, Hilger E, Krenn M, Paul A, Cetin H, Zimprich F. Frequency and clinical features of treatment-refractory myasthenia gravis. J Neurol. 2020;267(4):1004–11.
Schneider-Gold C, Hagenacker T, Melzer N, Ruck T. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019;12:1756286419832242.
Xin H, Harris LA, Aban IB, Cutter G. Examining the Impact of Refractory Myasthenia Gravis on Healthcare Resource Utilization in the United States: Analysis of a Myasthenia Gravis Foundation of America Patient Registry Sample. J Clin Neurol. 2019;15(3):376–85.
Veltsista D, Kefalopoulou Z, Tzartos J, Chroni E. Autoantibody profile in myasthenia gravis patients with a refractory phase. Muscle Nerve. 2022;65(5):607–11.
Feng HY, Wang HY, Liu WB, He XT, Huang X, Luo CM, Li Y. The high frequency and clinical feature of seronegative myasthenia gravis in Southern China. Neurol Sci. 2013;34(6):919–24.
Baggi F, Andreetta F, Maggi L, Confalonieri P, Morandi L, Salerno F, Bernasconi P, Montomoli C, Barberis M, Mantegazza R, et al. Complete stable remission and autoantibody specificity in myasthenia gravis. Neurology. 2013;80(2):188–95.
Zhang X, Yang M, Xu J, Zhang M, Lang B, Wang W, Vincent A. Clinical and serological study of myasthenia gravis in HuBei Province, China. J Neurol Neurosurg Psychiatry. 2007;78(4):386–90.
Niks EH, Kuks JB, Verschuuren JJ. Epidemiology of myasthenia gravis with anti-muscle specific kinase antibodies in The Netherlands. J Neurol Neurosurg Psychiatry. 2007;78(4):417–8.
Álvarez-Velasco R, Gutiérrez-Gutiérrez G, Trujillo JC, Martínez E, Segovia S, Arribas-Velasco M, Fernández G, Paradas C, Vélez-Gómez B, Casasnovas C, et al. Clinical characteristics and outcomes of thymoma-associated myasthenia gravis. Eur J Neurol. 2021;28(6):2083–91.
Thomsen J, Andersen H. Outcome Measures in Clinical Trials of Patients With Myasthenia Gravis. Front Neurol. 2020;11:596382.
Katzberg HD, Barnett C, Merkies IS, Bril V. Minimal clinically important difference in myasthenia gravis: outcomes from a randomized trial. Muscle Nerve. 2014;49(5):661–5.
Yin K, Feng L, Cheung WK. Context-Aware Time Series Imputation for Multi-Analyte Clinical Data. J Healthc Inf Res. 2020;4(4):411–26.
Mendoza M, Tran C, Bril V, Katzberg HD, Barnett C. Patient-acceptable symptom states in myasthenia gravis. Neurology. 2020;95(12):e1617–16171628.

No competing interests reported.

STROBEchecklistv4combined.doc

Download PDF

Editorial decision: Revision requested
15 May, 2024
Submission checks completed at journal
13 May, 2024
Editor assigned by journal
13 May, 2024
First submitted to journal
06 May, 2024

You are reading this latest preprint version

Clinical characteristics and outcome of treatment-refractory myasthenia gravis -a retrospective study

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

1. Introduction

2. Methods

2.1 Patients

2.2 Data collection

2.3 Diagnosis of refractory MG

2.4 Outcomes

2.5 Statistical analysis

3. Results

3.1 patients’ baseline characteristics

3.2 Treatment and outcomes

4. Discussion

5. Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1