Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis

Inclusion Criteria

• •Patients will be included in the trial based on the following criteria:
• •2. Subjects must either have the classic rash(es) of DM (heliotrope, Gottron sign or Gottron papules), possess one of the myositis-associated autoantibodies (e.g. anti-synthetase, anti-signal recognition particle (anti-SRP), anti-Mi-2, anti-PM-Scl, transcription intermediary factor 1-γ (anti TIF1-γ etc.), or have the diagnosis of PM agreed upon by a 3-member Adjudication Committee consisting of a rheumatologist, neurologist and neuromuscular pathologist.
• •3. Refractory myositis patients are defined (see Section 3.1.1) as having failed (or considered intolerant to) an adequate course of glucocorticoids or having failed glucocorticoids and at least one other immunosuppressive (IS) or immunomodulatory agent (e.g. methotrexate, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, cyclophosphamide, Intravenous immunoglobulin (IVIg), anti-tumor necrosis factor (anti-TNF) agents, and rituximab).
• •4. Subjects with an Manual muscle score (MMT-8) score ≤ 66 (see Appendix B) must also have at least 2 other core set measures meeting the criteria listed below.
• •5. Subjects with an MMT-8 score \> 66 must have at least 3 other core set measures meeting the criteria listed below and a global extramuscular visual analog score (VAS) score on the Myositis Disease Activity Assessment Tool ( MDAAT) ≥ 5cm on a 10cm scale.
• •6. Criteria for core set measures for study entry:
• •1. Patient global VAS with a minimum value of 2.0cm on a 10cm scale.
• •2. MD global VAS with a minimum value of 2.0cm on a 10cm scale.
• •3. Health Assessment Questionnaire (HAQ) disability index with a minimum value of 0.25
• •4. Elevation of at least one of the muscle enzymes (Creatine kinase (CK), aspartate aminotransferase (AST), alanine transaminase (ALT), aldolase, Lactate dehydrogenase (LDH) at a minimum level of 1.3x the upper limit of normal (ULN).
• •5. Global extramuscular disease activity score with a minimum value of 1.0cm on a 10cm VAS scale on the Myositis Disease Activity Assessment Tool (MDAAT).
• •7. If on prednisone, the dose must be stable for 4 weeks prior to the screening visit. Tapering of the prednisone dose will only be allowed after the subject meets the Definition of Improvement (DOI) or if safety/toxicity issues supervene.
• •1. Prednisone Tapering: Prednisone should be held constant without tapering or escalation (unless there is a serious adverse event or disease flare) until the subject has achieved the DOI. Then, tapering of prednisone may commence using a schedule approximating a 20-25% taper of the existing dose every 4 weeks based on the clinical judgment of the clinical site investigator. Prednisone tapering using the aforementioned guidelines can be commenced at any time if: (a) the patient achieves the DOI or (b) there are complications or circumstances that, in the clinical site investigator's opinion, necessitate the tapering of corticosteroids.
• •2. Prednisone at Entry: It is also recommended that patients be on less than 1mg/kg/day of prednisone at study entry.
• •3. Prednisone Dosing During Flare: If in the clinical site investigator's opinion there are complications or worsening of disease that necessitate an increase in the prednisone dose then the smallest reasonable increase should be considered.
• •8. If an immunosuppressive (IS) agent was discontinued prior to the screening visit there may be a washout as stipulated below or individualized according to the patients treating physician:
• •1. 4 week washout for methotrexate
• •2. 8 week washout for any other IS agent (e.g. azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil)
• •3. 3 month washout for leflunomide, IVIg or cyclophosphamide
• •4. 6 month washout for rituximab
• •5. 8 week washout for infliximab or adalimumab
• •6. 2 week washout for etanercept
• •7. 1 week washout for anakinra
• •9. If an IS agent is continued, the dose must remain stable for 4 weeks prior to enrollment and at least until the DOI is met or if safety/toxicity issues supervene. Concomitant IS medications permitted include methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, and tacrolimus. IVIg will also be allowed as an immunomodulatory agent. Careful patient safety monitoring along with American College of Rheumatology (ACR) guidelines for monitoring these medications will be employed if those toxicity monitoring laboratory studies are not already being assessed as part of this trial. No concomitant biologic agents are allowed (rituximab, anti-TNFs, abatacept) as well as cyclophosphamide or tofacitinib as concomitant immunosuppressive agents. Investigators will be certain to assess and classify adverse events as being secondary to either study drug as well as any concomitant immunosuppressive agent(s). That is, there should be attribution of the adverse event (AE) to the appropriate agent.
• •10. Normal organ function, except if abnormal due to the disease under investigation
• •11. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment.
• •12. Subject has provided written informed consent.