Abstract
Objective
The myopathy associated with anti-signal recognition particle (SRP) is a severe necrotizing immune-mediated disease characterized by rapidly progressive proximal muscle weakness, markedly elevated serum creatine kinase (CK) levels, and poor responsiveness to traditional immunosuppressive therapies. Reports on the efficacy of B cell depletion therapy for anti-SRP associated myopathy are mixed. We describe eight patients with anti-SRP associated myopathy and their response to treatment with the anti-CD20 monoclonal antibody rituximab.
Methods
We identified eight patients with myopathy who tested positive for anti-SRP antibodies by immunoprecipitation and were treated with rituximab as part of clinical care. We reviewed their medical records to assess clinical, serologic, and histologic characteristics and response to therapy. In five patients, serum was collected before and after rituximab therapy. Autoantibodies were detected by immunoprecipitation and quantitated by densitometry, and the percent decreases in anti-SRP autoantibody levels were calculated.
Results
Six of eight patients who had been refractory to standard immunosuppressive therapy demonstrated improved manual muscle strength and/or decline in CK levels as early as two months after rituximab treatment. Three patients sustained the response for twelve to eighteen months after initial dosing. All patients were continued on adjunctive corticosteroids, but dosages were substantially reduced after rituximab. Quantitative levels of serum anti-SRP antibodies also decreased after rituximab treatment.
Conclusions
B cell depletion therapy with rituximab is effective for patients with myopathy associated with anti-SRP. The substantial decrease in anti-SRP antibody levels after rituximab treatment also suggests that B cells and anti-SRP antibodies may play a role in the pathogenesis of this myopathy.
Myositis-specific or myositis-associated antibodies are detected in approximately 50% of patients with idiopathic inflammatory myopathies (IIM) and help to define subgroups of patients with certain distinguishing clinical features1–2. Anti-signal recognition particle (SRP) autoantibodies are myositis-specific antibodies found in 4–6% of patients with IIM 2–3. These antibodies are directed against SRP, a ribonuclear protein particle that regulates protein translocation across the endoplasmic reticulum membrane during protein synthesis. Studies have demonstrated that anti-SRP myopathy appears distinct from polymyositis (PM) and other idiopathic inflammatory myopathies by its clinical features and histopathology3–6. Patients with anti-SRP antibodies often present clinically with a severe myopathy characterized by markedly elevated serum creatine kinase (CK) levels and rapidly progressive proximal muscle weakness leading to significant disability. On histopathology, anti-SRP patients demonstrate a necrotizing myopathy without primary inflammation; however several studies have demonstrated MHC-1 immunostaining, and most histopathologic studies have found capillary pathology with deposition of the terminal components of complement (C5b-9), membrane attack complex.4–6
Anti-SRP myopathy also differs from other immune-mediated myopathies by its characteristically poor responsiveness to steroid monotherapy and conventional immunosuppressive therapies. Although the pathophysiologic role of B cells as causative agents in several autoimmune diseases is not entirely understood, several off-label studies have shown efficacy of the B cell depleting therapy rituximab, an anti-CD20 monoclonal antibody, in diseases that can be treatment refractory such as systemic lupus erythematosus (SLE)7, rheumatoid arthritis (RA)8, and systemic vasculitides9. B cell depletion therapy has also been an encouraging option for patients with PM, dermatomyositis (DM), and juvenile DM in several case series10–12. Thus far, reports of rituximab’s efficacy in treatment of anti-SRP myopathy have been mixed. A recent case report described poor clinical response to rituximab in two anti-SRP patients13. However, an earlier investigation by Lambotte et al. of two patients with refractory anti-SRP myopathy demonstrated marked and sustained clinical response to the combination of prednisone, plasma exchange, and repeated courses of rituximab.14
In this case series, we report the characteristics of eight patients with anti-SRP myopathy and their dramatic response to B cell depletion therapy when their disease was refractory to traditional therapeutic agents.
PATIENTS AND METHODS
Design
This is a retrospective case series review of eight patients with anti-SRP myopathy who were treated with rituximab at the Johns Hopkins Myositis Center.
Subjects
All patients had been evaluated as part of routine clinical care in the outpatient myositis clinic at the Johns Hopkins University Hospital or Johns Hopkins Bayview Medical Center in Baltimore, Maryland between 2006 and 2009. We identified and reviewed the medical records of eight patients who tested positive for anti-SRP antibodies and had been treated with rituximab.
Sera
Serum samples had previously been collected and banked at −80°C from all patients with probable or definite IIM according to the criteria of Bohan and Peter15 and from patients with conditions suggesting the diagnosis of myositis. Informed consent from study participants was obtained according to Institutional Review Board protocol.
Assessment of muscle disease
Strength had been assessed by one of two physicians at the Johns Hopkins Myositis Center through manual muscle testing and graded by the MRC scale. All patients were subsequently re-assessed by the same physician who performed the initial evaluation. Five patients had electromyographic and nerve conduction studies performed and interpreted by the Neuromuscular Division at Johns Hopkins Bayview Medical Center. Seven patients had undergone lower extremity MRI with T1 and T2 weighted STIR which was reviewed by the radiology department at Bayview Medical Center. Seven patients in this series had muscle biopsies performed and six of these were interpreted at Johns Hopkins Hospital by the Neuromuscular Pathology Laboratory.
Detection of anti-SRP 72, 54 and 19 antibodies by immunoprecipitation
cDNA clones encoding human SRP 54 and 19 were purchased from Origene (Rockville, MD); cDNA encoding human SRP 72 was cloned in the lab using HeLa cDNA and the cDNA encoding histidyl tRNA synthetase (Jo-1) was a kind gift from Drs Plotz and Raben (NIH, Bethesda, MD). All clones were sequence verified prior to use. 35S-methionine-labeled SRP proteins were generated from these cDNAs by coupled in vitro transcription and translation (IVTT) using a rabbit reticulocyte lysate-based system (Promega, Madison, WI). The radiolabeled protein products were immunoprecipitated as previously described16 with the patient serum samples described above (obtained pre- and post- rituximab treatment). The IVTT immunoprecipitation assay to detect anti-SRP antibodies was validated using reference sera known to be positive for those antibodies. Immunoprecipitates were electrophoresed on 10% or 12% sodium dodecyl sulfate-polyacrylamide gels, visualized by fluorography and the autoradiograms were scanned by densitometry. In each case, the percent decrease in autoantibody level after treatment was calculated.
Rituximab treatment
Patients were administered a standard dosing protocol of 1000 mg/m2 of intravenous rituximab infused once with a second dose repeated after two weeks. Patients were pre-treated with 100 mg intravenous solumedrol prior to infusions. One of the eight patients (Patient 4) received only one of the two infusions.
CASE REPORTS
Patient 1
A 20 year old African-American female presented six months after a diagnosis of mononucleosis when she began to experience falls, lower extremity weakness, dypshagia, a scaly erythematous neck rash, and new onset Raynaud’s phenomenon. The weakness rapidly progressed to the point that she was wheelchair-bound with grade 2/5 strength in the proximal upper and lower extremities. Laboratory testing revealed a markedly elevated CK at 56,000 IU/L and the presence of anti-Ro antibodies. Lower extremity MRI showed extensive edema, and electromyography was consistent with an irritable myopathy. Muscle biopsy showed a necrotizing myopathy with patchy endomysial and perimysial infiltrate and focal fiber degeneration. The presence of autoantibodies to SRP 72,54, and 19 in this serum was confirmed in our research laboratory by IVTT immunoprecipitation. The patient was treated with high dose intravenous and oral corticosteroids, azathioprine, and methotrexate with minimal improvement in strength, and CK remained elevated at 2710 IU/L. She was then treated with two doses of rituximab and continued on adjunctive methotrexate and prednisone. Four months after treatment with rituximab, CK had decreased to 622 IU/L and strength improved to grade 5/5 proximal and distal muscles. Eight months later, MRI shows mild muscle edema that is markedly improved. CD19 and CD20 counts remain suppressed.
Patient 2
A 34 year old African-American female, previously a competitive cheerleading coach, presented with rapidly progressive and severe proximal upper and lower extremity weakness, dypshagia, and nonspecific facial erythema. Strength testing was initially grade 4/5 and 3/5 proximal upper and lower extremities. Evaluation showed an elevated CK to 21,333 IU/L, MRI with profound muscle edema, and irritable myopathy on EMG. Muscle biopsy showed a necrotizing myopathy with no primary inflammation with degenerating and regenerating fibers, and the patient was diagnosed with polymyositis. Antibodies against SRP 72 and 19 were confirmed in this patient’s serum by IVTT immunoprecipitation. She was started on high dose prednisone at 80 mg orally twice daily along with methotrexate 25 mg weekly, monthly IVIg, and then azathioprine without benefit. Eventually, the patient became bedridden with proximal strength grade 2/5 and developed respiratory distress and severe dysphagia. She was hospitalized and received pulse dose intravenous solumedrol, IVIg, and Cytoxan but continued to deteriorate and was subsequently intubated for respiratory muscle weakness. She then received 5 plasmapheresis treatments and two doses of rituximab. Two months later, CK had decreased to 371 IU/L from 1000 IU/L and strength had improved to grade 3/5. She continued to improve in strength and was re-dosed with rituximab 6 months after her initial dose primarily to sustain her response. Eighteen months after initial dosing, CK has now normalized to 163 IU/L and the patient’s strength is grade 5/5 and 4/5 in proximal upper and lower extremities respectively. CD19 and CD20 counts are undetectable.
Patient 3
A 45 year old white female presented with a 3 year history of fatigue and proximal muscle weakness which rapidly progressed over months to an inability to feed herself with significant dysphagia. Initial CK was 5,148 IU/L. Muscle biopsy showed a severe necrotizing myopathy with no primary inflammation. IVTT immunoprecipitation testing showed antibodies against SRP 72, 54, and 19. The patient was given a diagnosis of PM and treated with high dose oral prednisone, methotrexate, and mycophenylate mofetil with no significant improvement in muscle strength. Azathioprine was tried briefly but caused severe gastrointestinal intolerance. Nine IVIg infusions provided no sustained effect and were discontinued when she developed a pulmonary embolus. Since no primary inflammation was seen on biopsy, the patient’s physicians discontinued steroid therapy and the patient’s strength precipitously declined until she was bed-bound and enrolled in hospice. Manual muscle strength was graded 1/5 proximal upper and lower extremities and CK was 550 IU/L. She was then treated with intravenous pulse steroids and rituximab. Two months after rituximab, biceps and hip flexor strength improved to grade 3/5 and CK decreased to 237 IU/L. Methotrexate was added as an adjunctive medication and after six months, and CD19 and CD20 counts were still undetectable. To sustain the clinical response, rituximab was re-administered for two doses. Eight months later, CD19 and CD20 counts remained suppressed, but the patient felt increased weakness and was administered a fifth dose of rituximab. Hip flexor strength then improved to grade 4/5, while proximal upper extremity and knee flexor strength substantially improved to grade 5/5. Nineteen months after the initial rituximab dose, CD19 and CD20 counts remain suppressed and CK has normalized to 126 IU/L.
Patient 4
A 72 year old white male presented with a 6 month history of generalized weakness in his arms and legs, muscle cramps and stiffness, and dysphagia to solids and liquids. Examination showed proximal muscle weakness in the neck, deltoids, and hip flexors grade 2/5 and diffusely atrophic muscles in the scapula, proximal arms, quadriceps, and pectoralis. Labs showed an elevated CK of 6885 IU/L and aldolase of 62 IU/L. Electromyography revealed an irritable myopathy and nerve conduction studies showed a mixed sensorimotor polyneuropathy. Extremity MRI demonstrated diffuse edema in medial, anterior, and posterior compartments with atrophy. Muscle biopsy showed a necrotizing myopathy with regenerating and degenerating fibers, myophagocytosis, and acute and chronic neurogenic atrophy with no primary inflammation. Sural nerve biopsy showed a mild active and chronic neuropathy with no inflammation. IVTT immunoprecipitation in our research laboratory showed antibodies against SRP 72 and 19. The patient was treated with high dose oral corticosteroids, IVIg, and plasma exchange with no substantial improvement in strength. He was then treated with one dose of rituximab. Within two weeks, CK had normalized to 22 IU/L. One month later, the patient developed pneumonia and congestive heart failure exacerbation and died in hospice.
Patient 5
A 21 year old African-American female presented with a 4 month history of rapidly progressive upper and lower extremity weakness and weight loss. Initial CPK was greater than 20,000 IU/L and muscle strength grade 1/5 in her upper and lower extremities. Extremity MRI showed widespread atrophy and muscle edema. EMG revealed an irritable myopathy. Muscle biopsy showed a necrotizing myopathy with atrophy, perivascular inflammation, and no primary inflammation. Antibodies against SRP 72, 54, and 19 were detected in this patient’s serum using IVTT immunoprecipitation. She was treated with intravenous and oral corticosteroids and CK decreased to 3000 IU/L, but strength minimally improved and she became wheelchair bound. Methotrexate and IVIg treatment yielded no improvement. She was then treated with rituximab. After 2 months, there was marked improvement in strength to grade 4-/5 and 2/5 proximal upper and lower extremities respectively and CK decreased to 1144 IU/L. MRI showed decrease in muscle edema. CD19 and CD20 counts were undetectable. Ten months later, CD19 and CD20 counts remained suppressed, but CK increased to 5600 IU/L. The patient was re-administered two doses of rituximab, and CK improved to 3,000 IU/L within three months.
Patient 6
A 26 year old African-American female presented with a one month history of progressively worsening proximal arm and leg weakness, dysphagia, scaling pruritic hand rash, new onset Raynaud’s phenomenon, and myalgias. Examination of muscle strength was graded initially 4/5 proximal upper and lower extremities. Laboratory data showed a markedly elevated CK at 20,180 IU/L and elevated aldolase of 46 IU/L. Electomyography revealed an irritable myopathy. MRI showed significant edema in the anterior and medial thigh muscles. Muscle biopsy showed a necrotizing myopathy with regeneration and degeneration but no inflammation. Commercial laboratory testing of myositis specific antibodies showed weakly positive anti-Ku. We confirmed the presence of anti-SRP 72 antibodies using IVTT immunoprecipitation. The patient was treated with high doses of intravenous and oral corticosteroid therapy, IVIg, methotrexate, and mycophenylate mofetil with progression of weakness to grade 3/5 and 2/5 in proximal upper and lower extremities respectively and persistently elevated CK at 2500 IU/L. She was then treated with 2 doses of rituximab. Within four months, CK had decreased to 1300 IU/L, half the value prior to rituximab, and by six months, strength had improved to grade 5/5 in proximal upper extremities and 3/5 in hip flexors. Repeat MRI showed decreased muscle edema. CD19 and CD20 counts continue to be suppressed six months after treatment.
Patient 7
A 57 year old Caucasian male with history of inflammatory polyarthritis for 20 years treated with methotrexate developed lower extremity weakness with bilateral knee inflammatory arthritis. Initial CK was 7,855 IU/L and EMG showed an irritable myopathy suggesting polymyositis. Patient elected not to have a muscle biopsy performed. Treatment was started with prednisone 60 mg daily, methotrexate 25 mg weekly, and eventually mycophenylate mofetil but CK remained elevated at 3,000 IU/L and weakness persisted with grade 4/5 proximal upper and lower extremity strength. IVTT immunoprecipitation in our research laboratory showed antibodies against SRP 72 and 54. The patient was treated with two doses of rituximab. Three months after treatment, CK had decreased to 1000 IU/L.
Patient 8
A 32 year old Caucasian female presented with progressively worsening weakness of the proximal upper and lower extremities, stiffness and myalgias, new onset Raynauds, fevers, weight loss, and nonspecific erythema at the neck and malar regions. Initial CK and aldolase were elevated at 8,495 IU/L and 147 IU/L respectively. Electromyography revealed an irritable myopathy. MRI demonstrated muscle edema of the anterior and posterior compartments. Muscle biopsy showed an inflammatory myopathy with scattered myophagocytosis, myofiber degeneration, and primary inflammation. Autoantibody testing using IVTT immunoprecipitation confirmed the presence of antibodies against SRP 54. The patient was started on prednisone 60 mg daily with a minimal improvement in strength. Azathioprine, methotrexate, and monthly IVIg treatments were administered, but CK remained elevated at 3,000 IU/L with continued weakness in the proximal upper extremities grade 4/5 and hip flexors grade 2/5. The patient was then administered two doses of rituximab. Six months after rituximab therapy, CK decreased to 2100 IU/L and CD19 and CD20 counts remained suppressed. Although proximal upper extremity weakness improved slightly to grade 5/5, lower extremity weakness persisted which necessitated alternative therapy.
Adverse Events
Rituximab was well tolerated in all patients. Patient #5 developed a herpes zoster infection three months after rituximab treatment which healed within two weeks. Patient #3 developed a facial abcess one month after rituximab that resolved after antibiotic treatment. One death occurred in patient #4 who developed pneumonia and a congestive heart failure exacerbation one month after rituximab treatment. It is unclear if rituximab contributed to the patient’s infection in the setting of older age and multiple comorbidities.
DISCUSSION
The present study is the largest case series to date of patients treated for anti-SRP associated myopathy with B cell depletion therapy. We have identified eight patients with anti-SRP antibodies who developed severe myopathies unresponsive to other agents and the majority showed a robust clinical response to rituximab treatment. This series suggests that B cell depletion therapy may be effective in patients with anti-SRP associated myopathy and especially in those with refractory disease.
The eight patients represented in this case series demonstrated similar clinical characteristics to anti-SRP patients described by others3,4,6(Table 1). The mean age of this cohort was younger at 37 years and was comprised of a larger proportion of African-Americans (50%) than has been reported in prior studies. The higher percentage of African-American subjects in our cohort could be due to our particular geographic area and referral base. Alternatively, our findings could suggest that African-Americans manifest a particularly severe myopathy and may be more responsive to rituximab treatment when compared to Caucasians, but further prospective studies are needed to support this. Clinically, all patients in our study presented similarly with rapidly progressive and severe proximal muscle weakness accompanied with myalgias and dysphagia. Several also had signs of distal or asymmetric weakness that is atypical of PM or DM. Generally, patients also had extremely high CK levels at presentation (mean maximum CK 18,900 IU) with either mild or no elevation in inflammatory markers (Table 2). Only two patients demonstrated autoantibodies other than anti-SRP, but none manifested symptoms of overlapping autoimmune disease. All patients demonstrated intense and widespread increase in STIR signal on muscle MRI reported as diffuse muscle or fascial edema, a finding that we have observed in patients with anti-SRP myopathy. Despite MRI findings of a highly inflammatory process, the histologic appearance of their muscle biopsies consistently demonstrated significant muscle necrosis with complete absence of primary inflammation. Consequently, the diagnosis of anti-SRP myopathy was often delayed in many patients due to the absence of inflammation on muscle biopsy.
Table 1.
Patient Demographics and Presenting Characteristics
| Patient | Age at Onset (Years) | Gender | Race* | ILD | Raynaud’s Phenomenon | Rash | Myalgia | Arthritis | Dysphagia | Weakness on Exam** |
||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PU | DU | PL | DL | A | ||||||||||
| 1 | 20 | F | AA | -- | + | + | + | + | + | + | + | + | − | + |
| 2 | 34 | F | AA | -- | -- | + | -- | -- | + | + | − | + | + | − |
| 3 | 42 | F | W | -- | -- | -- | -- | -- | + | + | + | + | − | − |
| 4 | 72 | M | W | -- | -- | -- | + | -- | + | + | + | + | + | + |
| 5 | 21 | F | AA | -- | + | -- | + | + | -- | + | + | + | − | + |
| 6 | 26 | F | AA | -- | + | + | -- | + | + | + | − | + | − | − |
| 7 | 51 | M | W | -- | -- | -- | + | + | + | + | − | + | − | − |
| 8 | 32 | F | W | -- | + | + | + | -- | -- | + | − | + | − | − |
Key: ILD = interstitial lung disease;
AA= African-American, W= Caucasian
PU = proximal upper extremity, DU= Distal upper extremity, PL=proximal lower extremity, DL=distal lower extremity
A= asymmetrical weakness. Weakness was defined as ≤ 4 on manual muscle strength testing
Table 2.
Laboratory, EMG, and Histologic Features of Anti-SRP-Myopathy
| Patient | Max CK (IU/l) | Max Aldolase (IU/l) | Elevated ESR/CRP | ANA (titer) | SRP+ (bands) | Positive Auto-antibodies | EMG irritable | Muscle Biopsy Features* |
||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PI | PVI | D | R | N | ||||||||
| 1 | 56,000 | 8.8 | +/-- | -- | + (72,54,19) | + Ro | + | -- | -- | + | -- | -- |
| 2 | 21,333 | 55.6 | --/-- | -- | + (72,19) | -- | + | -- | -- | --- | + | + |
| 3 | 3148 | 14.6 | --/+ | -- | + (72,54,19) | -- | N/A | -- | + | -- | + | + |
| 4 | 6885 | 62 | --/+ | -- | + (72,19) | -- | + | -- | -- | -- | + | + |
| 5 | 28,000 | 30 | +/-- | -- | + (72,54,19) | -- | + | -- | + | -- | + | + |
| 6 | 20,180 | 46 | +/-- | -- | + (72) | +Ku | + | -- | -- | -- | + | + |
| 7 | 7,855 | N/A | +/-- | N/A | + (72,54) | -- | -- | N/A | N/A | N/A | N/A | N/A |
| 8 | 8,495 | 147 | --/-- | -- | + (54) | -- | + | + | + | + | + | -- |
Key: CK= creatine kinase; ESR=erythrocyte sedimentation rate; CRP=C-reactive protein; ANA= anti-nuclear antibodies; SRP=signal recognition particle; EMG=electromyography; N/A = information not available
PI=primary inflammation; PVI=perivascular inflammation; D=degeneration; R=regeneration; N=necrosis
There has been substantial interest in the role of B cells in autoimmune disease given the success of the monoclonal anti-CD20 antibody rituximab in treatment of SLE, RA, and other processes that can be treatment refractory. Recently, B cell depletion therapy has also been effective in diseases with myositis-specific antibodies such as Jo-1 positive myopathy.11 Several studies have demonstrated that the levels of Jo-1 autoantibodies correlate with disease activity and may moderately decrease or disappear with successful therapy.4,11 Similarly, in our case series, we demonstrate that the levels of anti-SRP antibodies can be reduced substantially with rituximab therapy (Table 4). This suggests that B cells and anti-SRP antibodies may have a pathogenic role in the inflammatory process of these particular myopathies, and rituximab as B cell depletion therapy may serve to directly target this immune response.
Table 4.
Percent Decrease in SRP Autoantibody Levels After Rituximab Treatment*
| Patient | Anti-SRP 54 | Anti-SRP 19 | Anti-SRP 72 | Anti-Jo1 | Time (in months) from last Rituximab treatment to autoantibody analysis |
|---|---|---|---|---|---|
| 1 | 100 | 100 | 96 | NP | 4 |
| 2 | NP | 13 | 68 | NP | 2 |
| 3 | 50 | 57 | 47 | NP | 3 |
| 5 | 0** | 18 | 0 | NP | 9 |
| 6 | NP | NP | 42 | NP | 1 |
| Jo-1 control | NP | NP | NP | 0 | 18 |
Levels of autoantibodies were detected by immunoprecipitation using 35S-methionine labeled IVTT products, and quantitated as described in the methods section. Values of 100 and 0 represent complete and no disappearance of autoantibody, respectively.
In this patient, there was no loss of antibodies to SRP 54; rather, there was a 10% increase
NP= antibody not present in patient’s serum prior to Rituximab treatment
Serum from patients 4,7, and 8 were not tested for this analysis
In this study, treatment with rituximab resulted in a dramatic and sustained clinical improvement in the majority of patients with anti-SRP myopathy (Table 3). Prior to rituximab therapy, many of these patients had continued to clinically deteriorate with marked weakness and severe disability. Several were wheelchair or bed-bound and one had entered hospice despite maximal immunosuppression with multiple agents. One patient in particular (Patient 2) had developed severe respiratory muscle weakness requiring prolonged intubation even after treatment with high dose corticosteroids, methotrexate, azathioprine, cyclophosphamide, and plasma exchange. Now, eighteen months after receiving four total doses of rituximab with adjunct corticosteroid therapy, this patient is able to walk, independently perform all of her activities of daily living, and has returned to work. Her response is similar to the other patients we have reported, as six of eight patients showed marked improvement in strength and/or decline in CK levels as early as two months after receiving two doses of rituximab. Three patients were re-administered rituximab six to eight months after initial dosing primarily to sustain the benefits achieved with the initial doses. Three patients have maintained this clinical improvement for as long as 12–18 months since the initial dose. Manual muscle strength data was incomplete for two patients who were either lost to follow-up (patient 7) or died (patient 4); in these patients, clinical response to rituximab was demonstrated by a decline in CK levels. Despite a lack of inflammation on histology, all patients were continued on adjunctive corticosteroid treatment after rituximab dosing since the anti-SRP myopathy can be responsive to steroids. However, in all eight patients, the dosages of corticosteroids were able to be substantially reduced after treatment with rituximab (Table 3).
Table 3.
Summary of Response to B Cell Depletion Therapy and Outcome
| Patient | CK prior to therapy (IU/l) | Highest prednisone dose (mg/day) | Previous treatments | Doses of B cell depletion therapy | Lowest prednisone dose post therapy (mg/day) | Lowest CK post therapy (IU/l) | Outcome post B cell depletion and duration of remission |
|---|---|---|---|---|---|---|---|
| 1 | 2710 | 60 | AZA, MTX | 1000 mg IV × 2 doses | 20 | 622 | Decline in CK and improvement in strength for 10 months |
| 2 | 1000 | 160 | MTX, AZA, IVIg, Plasma exchange | 1000 mg IV × 4 doses | 5 | 163 | Normalization of CK and improvement in strength for 18 months |
| 3 | 550 | 40 | MTX, AZA, IVIg, MMF | 1000 mg IV × 5 doses | 15 | 126 | Normalization of CK and improvement in strength for 19 months |
| 4 | 1063 | 80 | IVIg, Plasma exchange | 1000 mg IV × 1 dose | 50 | 22 | No outcome data; died 1 month later from pneumonia and CHF |
| 5 | 2900 | 80 | MTX, IVIg | 1000 mg IV × 4 doses | 10 | 963 | Decline in CK for 12 months, re- dosed for increased CK |
| 6 | 2100 | 60 | MTX, MMF, IVIg | 1000 mg IV × 2 doses | 30 | 1144 | Improvement in strength and decline in CK for 9 months |
| 7 | 1250 | 60 | MTX, MMF | 1000 mg IV × 1 dose | N/A | 1080 | Decline in CK for 5 months |
| 8 | 3110 | 60 | AZA, MTX, IVIg, plasma exchange | 1000 mg IV × 2 doses | 15 | 2100 | Modest decline in CK after 6 months with persistent proximal lower extremity weakness |
Key: CK=creatinine kinase; MTX=methotrexate; AZA=azathioprine; IVIg=intravenous immunoglobulin; MMF=mycophenylate mofetil; N/A = information not available
Anti-SRP antibody levels were quantitated pre- and post-rituximab treatment in five patients (Table 4). Similar initial levels of anti-SRP autoantibodies were detected in all 5 patients prior to rituximab treatment. In four of the five patients, anti-SRP antibody levels decreased significantly after rituximab therapy. In those patients, the time between treatment and autoantibody analysis ranged from 1–4 months. Clinical treatment response in terms of manual muscle strength testing and/or decline in CK was robust and sustained in those four patients. Rituximab had no effect on anti-SRP antibody levels in one of the five patients (Patient 5); however, this patient also had the longest time period between autoantibody analysis and rituximab treatment (9 months). Although patient 5 demonstrated an initial clinical response to rituximab, she began to manifest increased CK levels two months after autoantibody analysis which prompted retreatment with rituximab 12 months after the initial dose. This suggests that the effect of rituximab may wane over time, and decreases in SRP autoantibody levels may be most accurately quantified when performed soon after rituximab administration.
We conclude that B cell depletion with rituximab may be an effective and often life-saving therapy for patients with anti-SRP myopathy. Given that the manifestations of this myopathy can be quite severe and refractory to standard medications, prompt recognition of the disease and aggressive treatment has become increasingly important to prevent irreversible muscle damage and atrophy. Further studies are needed to elucidate the underlying disease pathogenesis and the precise role of anti-SRP antibodies in this unique subset of myopathies.
Acknowledgments
Dr. Christopher-Stine’s work is supported by the NIH (grant K23-AR-053197). Dr. Casciola-Rosen’s work was supported by the NIH (R01-AR-044684). Dr. Mammen’s work was supported by the NIH (grant K08-AR-054783).
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