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Refractory anti-synthetase syndrome treated with rituximab
... Regarding the published case reports and case series, we identified 20 reports that describe a total of 65 patients with ASS-ILD [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. Stabilization or significant improvement in ILD was reported in most cases, while there was only one mortality linked to Pneumocystis jirovecii pneumonia [38]. ...
Objective
To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with antisynthetase syndrome and progressive interstitial lung disease (ASS-ILD).
Methods
Multicentre observational retrospective longitudinal study of a cohort of patients with ASS-ILD that started treatment with RTX due to recurrent or ongoing progressive ILD despite therapy with glucocorticoids and immunosuppressants.
Results
Twenty-eight patients were analyzed. Examining the entire study population, before treatment with RTX the mean decline in %pFVC and %pDLCO from the ASS-ILD diagnosis to the initiation of RTX treatment (T0) was -6.44% and -14.85%, respectively. After six months of treatment, RTX reversed the decline in pulmonary function test (PFT) parameters: ∆%pFVC +6.29% (95% CI: -10.07 to 2.51; p=0.002 compared to T0) and ∆%pDLCO +6.15% (95% CI: -10.86 to -1.43; p=0.013).
Twenty-four patients completed one year of therapy and 22 two years, maintaining the response in PFT: ∆%pFVC: +9.93% (95% CI: -15.61 to -4.25; p=0.002) and ∆%pDLCO: +7.66% (95% CI: -11.67 to -3.65; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 18% of cases. In 33% of patients who required oxygen therapy at the start of treatment, it could be discontinued.
The frequency of adverse events reached 28.5% of cases.
Conclusion
Based on our results, RTX appears to be effective as rescue therapy in most patients with recurrent or progressive ASS-ILD unresponsive to conventional treatment. The use of RTX was well tolerated in the majority of patients.
... 37 In the setting, multiple drugs have been reported to have a beneficial effect on lung disease progression, and these reports are congruent with our clinical experience. 38,39 However, we do not want to neglect to mention that these drugs are generally used in combination. For example, MMF is reported to be effective, but when reading the document carefully, one notes that this drug was added to a background scheme. ...
... Favorable responses to RTX have been reported in case reports and retrospective uncontrolled studies, in particular ASSD-ILD [118][119][120][121][122][123][124]. ...
Interstitial lung disease (ILD) is one of the most serious pulmonary complications of connective tissue diseases (CTDs) and it is characterized by a deep impact on morbidity and mortality. Due to the poor knowledge of CTD-ILD’s natural history and due to the difficulties related to design of randomized control trials, there is a lack of prospective data about the prevalence, follow-up, and therapeutic efficacy. For these reasons, the choice of therapy for CTD-ILD is currently very challenging and still largely based on experts’ opinion. Treatment is often based on steroids and conventional immunosuppressive drugs, but the recent publication of the encouraging results of the INBUILD trial has highlighted a possible effective and safe use of antifibrotic drugs as a new therapeutic option for these subjects. Aim of this review is to summarize the available data and recent advances about therapeutic strategies for ILD in the context of various CTD, such as systemic sclerosis, idiopathic inflammatory myopathy and Sjogren syndrome, systemic lupus erythematosus, mixed connective tissue disease and undifferentiated connective tissue disease, and interstitial pneumonia with autoimmune features, focusing also on ongoing clinical trials.
... [13,16] независимо от того, развивались ли обострения у пациентов или нет, вводили им поддерживающие дозы ритуксимаба (1000 мг, № 1) через 6 мес, что давало или стойкий эффект [16], или отодвигало сроки развития обострения на 10−14 мес относительно последнего курса [13]. В случаях недостаточного эффекта после 1 курса терапии при проведении повторных курсов (по 2000 мг) или в поддерживающих дозах (500−1000 мг) удавалось достичь полного ответа [14,15]. ...
The patient with polymyositis and antisynthetase syndrome treated with rituximab (Mabtera) is described. Rituximab was added to thehigh‑dose cyclophosphamide therapy due to an acute onset of the disease with a highly progressive interstitial lung disease and inability of the high‑dose corticosteroids therapy because of comorbidity. There was almost complete normalization of pulmonary and muscular pathological changes with more than 4‑fold decrease of anti‑Jo‑1 antibodies on the treatment. No complications and no side effects during rituximab therapy were noted. This case report demonstrates the positive effect of rituximab in combination with high‑dose cyclophosphamide in the treatment of acute AS syndrome. The results published in literature are discussed.
The lung is a common site of complications in systemic connective tissue diseases (CTD), and its involvement can present in several ways. Although it is generally thought that interstitial lung disease develops later on in CTD, it is often the initial presentation (“lung dominant” CTD). Interstitial lung disease (ILD) can be present in most types of CTD, including rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, polymyositis or dermatomyositis, Sjögren’s syndrome and mixed connective tissue disease. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD associated ILD (CTD-ILD) can differ greatly from that of other forms of ILD. Interstitial lung disease must be detected early in the course of collagen disorders by performing high-resolution computed tomography and pulmonary function tests. The pattern described on HRCT is predictive for treatment response and disease progression. Immunosuppression is the mainstay of treatment for ILD, although data from randomized controlled trials (RCTs) to support specific treatments are lacking. The management of patients with CTD-associated ILD is optimized by multidisciplinary collaboration.
As an essential component of the translation machinery, aminoacyl-tRNA synthetases (aaRSs) are indispensable for cell viability. In complex multicellular organisms, this fundamental importance of aaRSs is further expanded by their broad regulatory functions, and reflected by their extensive human disease connections. This chapter focuses on the disease connection of the group of aaRSs supporting protein synthesis in the cytoplasm, including GlyRS and LysRS that are also used for mitochondrial translation. To date, three major disease types have been linked directly to cytoplasmic aaRSs: first, an autoimmune antisynthetase syndrome (ASS) characterized by the presence of autoantibodies targeting one of eight different aaRSs; second, a peripheral neuropathy, Charcot-Marie-Tooth disease (CMT) caused by dominant, mono-allelic mutations in six different aaRSs; and third, severe multi-organ disorders, often accompanied with developmental delays, caused by recessive, bi-allelic mutations in almost all cytoplasmic aaRSs. This chapter will cover broadly each of these types, with a lesser focus on CMT. An interesting feature of cytoplasmic aaRSs in complex organisms is the formation of a multi-synthetase complex (MSC), containing nine aaRSs and three non-enzymatic scaffold proteins. We note a general trend that MSC components are more likely to be involved in recessive diseases, whereas the freestanding aaRSs are predominantly linked to the dominant CMT disease and the autoimmune ASS. GlyRS and LysRS appear to be more susceptive to mutational impact, possibly due to their dual use for cytosolic and mitochondrial protein synthesis. Nevertheless, non-enzymatic functions of aaRSs are also linked to diseases as suggested by studies on ASS and CMT.
Introduction
The antisynthetase syndrome is a rare autoimmune disease described by the presence of inflammatory myositis, interstitial lung disease and antibodies against aminoacyl-transfer RNA synthetases. Interstitial lung disease can be the only manifestation in the absence of an inflammatory myositis. Other clinical signs are Raynaud phenomenon, hyperkeratotic skin lesions, fever and inflammatory polyarthritis.
Case presentation
We report the case of a 64-year old woman who complained of a dry cough, progressive dyspnea and arthralgia since 2 years, with no other systemic symptoms. High resolution computed tomography (HRCT) of the thorax showed the presence of bilateral ground glass opacities, reticular opacities and some traction bronchiectasis. Further biochemical testing revealed the presence of anti-PL12 antibodies.
Management
The diagnosis of antisynthetase syndrome was made and the patient was treated with steroids and azathioprine with a good response.
Conclusion
The search for antisynthetase antibodies should always be considered in patients with an interstitial lung disease without any other clinical symptoms or signs of an underlying connective tissue disease.
We present a case of pulmonary involvement associated to idiopathic inflammatory myopathy in a relatively homogenous clinical profile known as antisynthetase syndrome. This syndrome is characterized by myositis, arthralgias/arthritis, interstitial lung disease, fever, mechanic's hands, and Raynaud's phenomenon. Autoantibodies against aminoacyl-tRNA synthetases are associated, with anti-Jo-1 being the one most commonly found. The clinical appearance of pulmonary involvement is heterogeneous, slowly progressive or acute. Myositis precedes or is concurrent with the development of lung disease in the majority of cases, but the occurrence of lung involvement before myositis occurs in more than one third of cases. Therapy of these respiratory manifestations varies with the kind of clinical onset of the disease and with the level of functional impairment and must be personalized on the basis of clinical, functional and radiological findings of the follow up.
Clinical features of patients with anti-aminoacyl-tRNA synthetase-positive interstitial pneumonia are as follows: nonproductive cough; elevated levels of serum KL-6, surfactant protein-D, and surfactant pro-tein-A; decrease in vital capacity, total lung capacity, residual volume, and diffusing capacity of the lung for carbon monoxide; and a high percentage of Bron-choalveolar lavage fluid (BALF) lymphocyte; low BALF-CD4/8 ratio; good response to corticosteroid or immunosuppressant therapy; and good prognosis.
Interstitial lung disease (ILD) is the major determinant of morbidity and mortality in the anti-synthetase syndrome (ASS). Here we have retrospectively assessed 11 ASS patients with ILD treated with the anti-CD20 mAB rituximab at our tertiary referral hospital.
Data on clinical and laboratory parameters, lung imaging by high-resolution CT thorax and pulmonary function tests were collected from patient examinations done up to 6 months before rituximab was initiated, and at 3 and 6 months post-treatment.
All the 11 ASS patients had severe and progressive ILD and most of them had previously failed on cyclophosphamide and/or other immuno-modulating agents. Rituximab appeared to stabilize and/or improve the ILD in 7 of 11 ASS patients during the first 6 months after treatment. The rituximab treatment appeared to decrease the serum level of anti-Jo-1 antibodies, but the decrease was most often modest. One patient developed a fatal infection 3 months after the last infusion with rituximab. In the other ASS patients, the treatment was well tolerated.
This retrospective case series indicates a short-term beneficial effect of rituximab in ASS. Prospective, controlled studies are needed to validate this finding and further assess safety issues.
To test the hypothesis that B cells play a role in the pathophysiology of dermatomyositis (DM) by examining the effect of B cell depletion in patients with symptomatic DM. Patients were treated with rituximab, a CD20+ B cell-depleting monoclonal antibody.
This was an open-label uncontrolled pilot trial in 7 adult patients with DM, 6 of whom had longstanding illness that was responding inadequately to a number of currently available immunosuppressive agents. All patients received 4 intravenous infusions of rituximab given at weekly intervals. Patients were followed up for up to 1 year without further treatment with rituximab. One patient was lost to followup. The principal efficacy outcome was muscle strength, measured by quantitative dynomometry.
All 6 evaluable patients exhibited major clinical improvement, with muscle strength increasing over baseline by 36-113%. Maximal improvements in muscle strength occurred as early as 12 weeks after the initial infusion of rituximab. CD20+ B cells were effectively depleted in all patients by 12 weeks. Four patients experienced a return of symptoms that coincided with the return of B cells before the 52-week end point. Two patients maintained their increased muscle strength at 52 weeks, and 1 of these patients maintained this strength even after the return of B cells. Other symptoms of DM, including rash, alopecia, and reduced forced vital capacity, improved markedly in patients with these symptoms. Rituximab was well tolerated, with no treatment-related severe or serious adverse events during the observation period of this study.
This small open-label study of DM patients treated with rituximab provided sufficiently encouraging results to justify a more formal evaluation of the value of B cell depletion therapy in the treatment of DM.
We describe response to rituximab treatment of refractory inflammatory myopathy. Three patients with long-standing polymyositis (PM) or dermatomyositis (DM) poorly responsive to prednisone combined with several immunosuppressants were given intravenous rituximab 1,000 mg on Days 0 and 14. Prior to rituximab, each had significant proximal weakness with creatine phosphokinase (CPK) elevation to>3 times the normal upper limit (range 789-3,123 U/l). Patients were receiving prednisone plus methotrexate (MTX) or azathioprine. CPK decrease was observed 1 month post-infusion, with normalization of levels averaging 4.6 months (range 2.6-7.7 mo). Muscle strength improved in all, with strength returning to normal in 2. Average daily prednisone dose decreased from 16.7 mg (range 10-20 mg) to 4 mg (range 0-7 mg) after infusion. MTX dose was tapered by 50% in 2 patients. The third patient eventually discontinued all additional therapies. Percentage of CD19+ cells in each were suppressed at 0-1% 5 to 6 months after infusion (normal 5-21%). Elevated CPK with return of clinical symptoms occurred in 2 patients 6 and 10 months post-infusion, requiring rituximab retreatment. CD19+ cells remained suppressed at 1% in one patient, but were almost normal at 4% in the other. The third patient remains disease-free 12 months after initial treatment, even though her CD19+ cells are now normal at 8%. Thus, short-term beneficial effects with rituximab were observed in patients with DM and PM. However, the need for retreatment did not correlate with levels of CD19+ cells.
To report the efficacy and toxicity of rituximab in the treatment of refractory polymyositis.
Adult patients with active polymyositis as evidenced by persistent proximal muscle weakness, elevated creatine kinase (CK) level, and features of active myositis on electromyography who were refractory to corticosteroids and at least 2 other immunosuppressive agents were recruited. While immunosuppressive agents were continued, rituximab (375 mg/m2) was given by intravenous infusion weekly for 4 consecutive weeks. Patients were followed up 4-weekly for serial assessment of muscle power, serum muscle enzymes, physician's and patient's global impression of disease activity, disability, and quality of life scores.
Four patients (3 women, 1 man) were studied. The mean age was 53 +/- 11 years and the mean duration of polymyositis was 4.8 +/- 3.3 years. All had persistently active myositis for at least 2 years. At Week 28, significant improvement in the mean proximal muscle power scores and reduction in CK levels in comparison to baseline were observed. Two patients had return of full muscle power with significant drop in CK level. There was a trend of improvement in disability scores and both the mental and physical components of the Medical Outcomes Study Short Form-36 Health Survey scores. Rituximab was well tolerated.
Rituximab is an option to be considered in refractory polymyositis, but further controlled trials are necessary to confirm its efficacy.