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05/01/23
Adel Abd Elsalam Adel Abd Elsalam ..Faculty of Medicine .Faculty of Medicine .Mansoura UneverisityMansoura Uneverisity
Treatment of recurrent and resistant dermatomyositis and
polymyositis in adults
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Nailfold capillaries
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INTRODUCTIONINTRODUCTION Dermatomyositis (DM) and polymyositis Dermatomyositis (DM) and polymyositis
(PM) are two classic forms of inflammatory (PM) are two classic forms of inflammatory myopathy. Most patients respond to initial myopathy. Most patients respond to initial therapy and some achieve sustained disease therapy and some achieve sustained disease control either off all therapy or with low control either off all therapy or with low dose maintenance therapy. dose maintenance therapy.
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There are two additional patterns of responseThere are two additional patterns of response:: Recurrent disease Recurrent disease -- After achieving disease After achieving disease
control with treatment, some patients experience control with treatment, some patients experience disease recurrences (flares) during or after the disease recurrences (flares) during or after the period of medication tapering.period of medication tapering.
Resistant disease Resistant disease -- The disease is considered refractory if a patient has not responded after taking an adequate dose of steroids plus one other immunosuppressant for an adequate duration (3m) ..
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RECURRENT DISEASERECURRENT DISEASE; ; 11stst scenario scenario;Flare at more than 10 mg/day ;Flare at more than 10 mg/day
of prednisone - Disease flares at such doses of prednisone - Disease flares at such doses of prednisone require one of two actionsof prednisone require one of two actions;;
1-Addition of a glucocorticoid-sparing 1-Addition of a glucocorticoid-sparing drug if neither drug if neither azathioprine nor nor methotrexate has been used. has been used.
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2-Treatment of the flare as a case of resistant disease if the patient is already taking either azathioprine or methotrexate Action, a higher dose of prednisone, generally in the range of 1 mg/kg per day, will be required to reestablish disease control
22ndnd scenario scenario;Flare at 10 mg/day of ;Flare at 10 mg/day of prednisone or less — If a disease flare or less — If a disease flare occurs at a prednisone dose of 10 mg/day or occurs at a prednisone dose of 10 mg/day or lessless..
there are two options that are USUALLY there are two options that are USUALLY USED:USED:
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1-Increase in 1-Increase in prednisone to the lowest dose to the lowest dose required to reestablish disease control. This required to reestablish disease control. This dose is based upon the severity of the dose is based upon the severity of the patient's clinical findings. If the disease patient's clinical findings. If the disease flare is detected early, the dose required flare is detected early, the dose required may be significantly lower than 1 mg/kg per may be significantly lower than 1 mg/kg per day. The usual minimum dose is 20 mg/dayday. The usual minimum dose is 20 mg/day
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CONTINUE
Once disease control is restored, slower Once disease control is restored, slower tapering than was used during the initial tapering than was used during the initial course. Some patients are maintained on course. Some patients are maintained on low dose low dose prednisone (eg, 5 mg/day) for one (eg, 5 mg/day) for one year or year or more.more.
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33rdrd scenario scenario;Flare off prednisone but on a ;Flare off prednisone but on a glucocorticoid-sparing drug glucocorticoid-sparing drug ..
There are There are two options in such patientstwo options in such patients; ; 1-Prednisone is reinstituted at the lowest dose 1-Prednisone is reinstituted at the lowest dose
required to reestablish disease control. The dose required to reestablish disease control. The dose selected is based upon the severity of the patient's selected is based upon the severity of the patient's clinical findings, and may be significantly lower clinical findings, and may be significantly lower than 1 mg/kg if the disease flare is detected early. than 1 mg/kg if the disease flare is detected early. The usual minimum dose is 20 mg/day.The usual minimum dose is 20 mg/day.
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continue
2-The glucocorticoid-sparing drug can be 2-The glucocorticoid-sparing drug can be changed from azathioprine to changed from azathioprine to methotrexate or vice versa.methotrexate or vice versa.
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RESISTANT DISEASE Multiple options exist for treating patients who Multiple options exist for treating patients who
do not respond adequately to glucocorticoids do not respond adequately to glucocorticoids plus azathioprine or methotrexate. Evidence of plus azathioprine or methotrexate. Evidence of clinically significant benefit is greatest with clinically significant benefit is greatest with rituximab and intravenous immune globulin rituximab and intravenous immune globulin (IVIG). Priority for using rituximab first in this (IVIG). Priority for using rituximab first in this setting, and then trying IVIG if rituximab fails.setting, and then trying IVIG if rituximab fails.
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other therapies must be considered after other therapies must be considered after excluding myositis mimicsexcluding myositis mimics::
1- dystrophies 1- dystrophies 2-Endocrinopathies eg thyroid dis.2-Endocrinopathies eg thyroid dis. 3-malignancy 3-malignancy
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Multiple options exist for treating patients who do not respond adequately to glucocorticoids plus either azathioprine or methotrexate; include:
-Rituximab -Intravenous immune globulin (IVIG) -Calcineurin inhibitors (Cyclosporine, Tacrolimus). -Mycophenolate mofetil- Cyclophosphamide -Tumor necrosis factor inhibitors -Combination therapy with azathioprine and methotrexate
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Rituximab targets CD20-positive cells, leading in most patients to the• depletion of B cells in the serum within several weeks of administration. The largest randomized trial to date in myositis, the Rituximab in• Myositis (RIM trial) enrolled 200 adult and pediatric DM or PM refractory to steroids and an additional immunosuppressant. 83% of patients met the IMACS (International Myositis Assessment and• Clinical Studies Group) definition of improvement. Predictors of improvement with rituximab included the presence of an• anti-synthetase antibody, anti-Mi-2, juvenile dermatomyositis and lower physician global damage scores
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The trend with the use of rituximab IVI is either:- one gram dose one week apart. 1g on Day 0 and Day 14 (used in RIM study),
375 mg/m2 BSA once weekly times four doses. Rituximab
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Conclusion.
Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the definition of improvement. The role of B cell–depleting therapies in myositis warrants further study.
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Intravenous Immunoglobulin If rituximab is not effective, IVIG is the second-line agent for the• treatment of resistant DM (Grade 2B). The 2012 American Academy of Neurology guidelines support the use of IVIG for refractory DM but found evidence insufficient to support or refuse its use in PM. The expense of this treatment is an important consideration in its long-term use. It acts fairly rapidly to bring a clinical response, and should be considered in cases of rapid deterioration despite steroids.
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IVIG is an important agent in the setting of:- -esophageal involvement -patients with contraindications to immunosuppressants, - refractory lung disease. -statin-associated immune-mediated necrotizing myopathy• -calcinosis.
Lancet. 2003 Arthritis Care Res. (2010) 62:1748–1755. Joint Bone Spine (2014) 81:79–82. Joint Bone Spine. (2013) 80:108–109. Intravenous Immunoglobulin
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Usually given with Prednisone (≈25 mg/day) and a monthly infusion of either:- IVIG (2 g/kg) for 3 months, plus one or more additional therapies, including :- methotrexate, azathioprine, cyclophosphamide, cyclosporine, chlorambucil, plasmapheresis, lymphapheresis, or total body irradiation. Or IVIG (1 g/kg per day for two days per month for 4-6 months).
Clinical Guidelines for Immunoglobulin Use (second edition), Dept of Health, May 2008 Intravenous Immunoglobulin
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Rituximab is better IVIG The reasons for favoring rituximab over IVIG, are the following:1- Rituximab appears to be effective in CTD resembling DM and PM, such as SLE and RA.2- If effective, rituximab may be more likely to lead to a prolonged period of disease control. 3-Many patients who respond to IVIG require continued treatments on a monthly basis•4-Although expensive, rituximab is cheaper than IVIG
Arthritis Rheum 2013 Rituximab & IVIG
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Calcineurin inhibitors The calcineurin inhibitors, which include cyclosporine and tacrolimus, achieve their effects by interfering with T cell function. Data on the use of calcineurin inhibitors in DM and PM are limited to retrospective case series and anecdotal reports.
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Cyclosporine cyclosporine has been suggested for both primary therapy and resistant disease, including interstitial lung disease In one report, six patients previously resistant to methotrexate, azathioprine, cyclophosphamide, and/or IVIG underwent treatment with a mean daily cyclosporine dose of 3.5 mg/kg . Over the median six month course of treatment with cyclosporine, the mean daily prednisone dose was reduced by 75 percent. All six patients demonstrated improved strength in the shoulder girdle; four had stronger hip flexor muscles.
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TACROLIMUS Used in a limited number of patients. The optimal dose for this• indication is not certain. In one report, tacrolimus (0.075 mg/kg/day in two divided doses) was effective in a series of 8 patients with refractory PM complicated by ILD. Strength normalized in 5/8 anti-Jo-1 antibody-positive patients and improved in the two anti-SRP positive patients. The mean CK declined from 3114 to 87 IU/mL. 3/5 patients with ILD also showed improvement in pulmonary function.•
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Conclusion: For ILD that is refractory to glucocorticoids plus either azathioprine or methotrexate, tacrolimus (0.2 mg/kg/day in divided doses)is use as the next agent (Grade 2C). The limited evidence available suggests that tacrolimus offers some advantage over cyclosporine (3.5 mg/kg/day) in efficacy, but larger studies are required before definitive conclusions are possible.
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MYCOPHENOLATE MOFETIL MMF (1 - 1.5 g twice daily) is a reasonable alternative if rituximab and IVIG have failed.• Clinicians must be alert to the possibility of opportunistic infection
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CYCLOPHOSPHAMIDE IV cyclophosphamide at doses ranging from 300 - 800 mg/m2 every four weeks plus prednisone. For at least six courses. Remission rates are high among patients who tolerate cyclophosphamide. Because of their substantial side effect profiles, it is wise to reserve alkylating agents (cyclophosphamide and chlorambucil) for severe refractory myositis with life-threatening organ involvement (Grade 1C).
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TNF-a inhibitors Preliminary data with anti- TNF therapy are not very promising• Hak et al., 2011 suggested not using TNF inhibitors in DM or PM, unless all other treatment options have failed (Grade 2C).•
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Combination therapy Prednisone with azathioprine (up to 200 mg/day) and methotrexate (up to• 25 mg/week) hold some potential for efficacy in patients with resistant disease. However, the risk of treatment-related morbidity when using both of• these medications together mandates the utmost care in monitoring patients for cytopenias and other adverse effects.
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APPROACH TO REFRACTORY SKIN DISEASE Therapy of cutaneous disease of DM is often difficult. Sun avoidance and sun protective measures (for photosensitivety). antipruritics, and topical corticosteroids or topical calcineurin inhibitors. Hydroxychloroquine and chloroquine. Methotrexate & Small case series or individual reports of successful management with leflunomide have recently appeared in the literature.
Callen JP, Wortmann RL; Dermatomyositis. Clin Dermatol. 2006
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Patients who fail to respond to these conventional interventions or who relapse after an initial response require the initiation of more aggressive immunosuppressive or immunomodulatory drug therapies.- IVIG not only benefits the muscle but also clears the skin lesions, -recently, MMF are reported to be useful. -Rituximab may prove useful in the treatment of muscle disease & has had mixed results in treatment of skin disease. -recently, efalizumab has been reported to be useful for skin disease. Sirolimus may also be of use in some patients.
Dalakas MC. Nat Rev Rheumatol.2010 APPROACH TO REFRACTORY SKIN DISEASE
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Calcinosis Cutis Cases of calcinosis may respond to .diltiazem , low- dose warfarin ,probenecid , alendronate , colchicine , intralesional corticosteroids, IVIG, or electric shock wave lithotripsy However, none of these therapies have been shown to be consistently
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SUMMARY AND RECOMMENDATIONS
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Recurrent disease
•
For patients who experience disease flares after the achievement of disease control, there are four specific scenarios.•1-For disease flares at more than 10 mg/day of prednisone, we suggest the addition of either azathioprine or methotrexate (if not already used) or treatment of the patient as a case of resistant disease (Grade 2C). (See 'Resistant disease' above.)•
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• 2-For disease flares at 10 mg/day of prednisone or less, we suggest increasing the prednisone to the lowest dose required to reestablish disease control and/or increasing the azathioprine or methotrexate dose, if this has not been maximized already (Grade 2C).
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• 3-For disease flares off prednisone but on a glucocorticoid-sparing drug, we suggest reinstituting prednisone at the lowest dose required to reestablish disease control and/or changing the glucocorticoid-sparing medication from azathioprine to methotrexate or vice versa (Grade 2C).
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• 4-Flare off all immunosuppressive medication, we suggest reinstituting prednisone with an initial daily dose that varies according to relapse severity (Grade 2C). The minimum starting dose of prednisone is 20 mg/day. In addition, a glucocorticoid-sparing drug should be resumed or started
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Resistant disease• Multiple options exist for treating patients who do not respond adequately to glucocorticoids plus either azathioprine or methotrexate. Options for the treatment of resistant disease, each of which is described above, include:• Rituximab• Intravenous immune globulin (IVIG)• Cyclosporine• Tacrolimus• Mycophenolate mofetil• Cyclophosphamide• Tumor necrosis factor inhibitors• Combination therapy with azathioprine and methotrexate
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