Rituximab for the Treatment of Refractory Inflammatory Myopathies and Refractory Myasthenia Gravis
Rituximab for the Treatment of Refractory Inflammatory Myopathies and Refractory Myasthenia Gravis
The traditional treatment of inflammatory myopathies (IM) and generalized myasthenia gravis
 (MG) is immunosuppressive therapy, usually beginning with corticosteroids. However, up to 70%
 of treated patients show an incomplete response, including 10 - 30% who are unresponsive.
 Corticosteroids and other immunosuppressive therapies presented also many side effects. We
 propose to evaluate in a pilot, open, prospective, multicentric, phase II study, the interest
 of rituximab in the treatment of patients with primary IM associated with specific AAb
 (anti-synthetase and anti-SRP AAbs), or MG (with anti-AchR AAbs), refractory to conventional
 therapies. Twenty fourth patients with primary IM (12 with anti-synthetase, 12 with anti-SRP
 AAbs), and 12 with MG will be included in the study.
Rituximab, a chimeric monoclonal antibody specific for human CD20, which targets B
 lymphocytes, has been first developed as biotherapy for the treatment of B lymphoma. In this
 context, hundred thousands patients received this drug, with a very good tolerance. Recently,
 interest has grown in the pivotal role of B cells for auto-immune humorally mediated
 diseases. Rituximab could then be a potential new biological treatment for such diseases,
 especially for patients refractory to conventional therapies. As a Muscular Diseases Centre,
 we have a large recruitment of patients with inflammatory myopathies (IM) and myasthenia
 gravis (MG). Although the physiopathogenesis of these two conditions differ, both can be
 associated with specific auto-antibodies (AAbs) and their therapeutic management is almost
 similar. The traditional treatment approach to IM and generalized MG is immunosuppressive
 therapy, usually beginning with corticosteroids. However, up to 70% of treated patients show
 an incomplete response, including 10 - 30% who are unresponsive. We propose to evaluate in a
 pilot, open, prospective, multicentric, phase II study, the interest of rituximab in the
 treatment of patients with primary IM associated with specific AAb (anti-synthetase and
 anti-SRP AAbs), or MG (with anti-AchR AAbs), refractory to conventional therapies.

 Inclusions criteria are IM (as defined by the 119th European Neuromuscular Centre workshop)
 or generalised MG (as defined by the Texas Clinical Classification System) associated with
 specific AAbs (anti-synthetases (JO1, PL7 or PL12), or anti-SRP for primary IM, and anti-AchR
 for MG) and refractory to conventional treatments defined as an inadequate response to, or
 intolerable side effects with conventional treatments, such as corticosteroids, azathioprine,
 methotrexate, cyclophosphamide, cyclosporine, IgIV and/or plasma exchange.

 The therapeutical schema is rituximab 1000 mg, 2 times (at day 0 and 15), followed by one
 single injection (1000 mg) 6 months latter and end of follow up at 1 year.

 The efficacy is evaluated by an improvement of Kendall's muscular testing or MG muscular
 score at month 12. Secondary criteria include Kendall's muscular testing or MG muscular score
 at day 21 and month 7, quality of life auto-questionnaire (SF 36), evolution of CK levels and
 AAb titers.

 Twenty fourth patients with primary IM (12 with anti-synthetase, 12 with anti-SRP AAbs), and
 12 with MG will be included in the study. If a success is observed in at least 6 patients, it
 will be possible to conclude that the response rate is above 25% (lower 90% confidence
 interval for observed response rate 50%).
Inclusion Criteria:

 -  For myositis III. Idiopathic myositis

 1. Myositis as defined by the 119th ENMC:

 1. Proximal myopathy with weakness

 2. Subacute or insidious onset over 18 years

 3. Myogenic syndrome on EMG (optional)

 4. Muscle fibre necrosis and regeneration and/or inflammatory cell infiltrate
 on muscular biopsy

 2. Specific AAbs : anti-synthetases (anti-JO1, anti-PL7, or anti-PL12), or anti-SRP.

 IV. Refractory to the conventional treatments Resistance to conventional
 treatments is defined as an inadequate response to, or intolerable side effects
 with conventional treatments, such as corticosteroids, azathioprine,
 methotrexate, cyclophosphamide, cyclosporine, IgIV and/or plasma exchange. At
 least one or more of these drugs or therapeutical approaches (used alone or as a
 combination) must have been unsuccessfully tested before inclusion. Inadequate
 response is defined as the lack of improvement and/or the degradation of
 evaluation parameters (defined bellow) despite these conventional therapies, that
 led to a modification or a reintroduction of treatment.

 -  For myasthenia III. Generalised MG

 Generalised seropositive MG as defined by the Texas Clinical Classification System:

 1. Extraocular muscle weakness quantified with MG muscle score (MMS), whose inter and
 inter observer reproducibility has been demonstrated [44].

 2. Specific AAbs : anti-AchR IV. Refractory to the conventional treatments Resistance to
 conventional treatments is defined as an inadequate response to, or intolerable side
 effects with conventional treatments, such as corticosteroids, azathioprine,
 methotrexate, cyclophosphamide, cyclosporine, IgIV and/or plasma exchange. At least
 one or more of these drugs or therapeutical approaches (used alone or as a
 combination) must have been unsuccessfully tested before inclusion. Inadequate
 response is defined as the lack of improvement and/or the degradation of evaluation
 parameters (defined bellow) despite these conventional therapies, that led to a
 modification or a reintroduction of treatment

 Exclusion Criteria:

 -  Other muscular diseases, such as:

 1. Inclusion body myositis

 2. Macrophagic myofasciitis

 3. Inherited myopathies

 -  Secondary IM to one other connective tissue disorders

 1. Systemic scleroderma (ARA and/or "LEROY AND MEDSGER" criteria)

 2. Sjögren's syndrome (European criteria)

 3. Systemic lupus erythematosus (ACR criteria)

 4. Rheumatoid arthritis (ACR criteria)

 5. Mixed connective tissue disease (ACR criteria)

 -  Other myasthenic syndrome, such as:

 1. Non generalised, ocular MG

 2. Lambert Eaton syndrome

 3. MG associated with malignant thymoma

 4. Inherited myasthenic syndrome

 -  Cancer (or cancer-associated myositis)

 -  Age < 18 years

 -  Pregnancy

 -  HIV seropositivity

 -  Evolutive infection (B, C hepatitis, tuberculosis)

 -  Lack of approved consent