Gottron’s sign is differentiated from SLE in which the rash is typically between the joints.
Upper left is normal. Upper right is scleroderma with dilation of isolated capillary loops with loss of surrounding structures. The lower left is an adult dermatomyositis with distortion of normal architecture, alteration in morphology of blood vessels, including dilated enlarged giant loops. The lower right child dermatomyositis with dilated capillary loops and arborized clusters.
Treatment of recurrent and resistant dermatomyositis and polymyositis in adults
Adel Abd ElsalamAdel Abd Elsalam ..
Faculty of Medicine .Faculty of Medicine .
Mansoura UneverisityMansoura Uneverisity
Treatment of recurrent and
resistant dermatomyositis and
polymyositis in adults
Dermatomyositis (DM) and polymyositisDermatomyositis (DM) and polymyositis
(PM) are two classic forms of inflammatory(PM) are two classic forms of inflammatory
myopathy. Most patients respond to initialmyopathy. Most patients respond to initial
therapy and some achieve sustained diseasetherapy and some achieve sustained disease
control either off all therapy or with lowcontrol either off all therapy or with low
dose maintenance therapy.dose maintenance therapy.
There are two additional patterns ofThere are two additional patterns of
Recurrent diseaseRecurrent disease -- After achieving diseaseAfter achieving disease
control with treatment, some patientscontrol with treatment, some patients
experience disease recurrences (flares) duringexperience disease recurrences (flares) during
or after the period of medication tapering.or after the period of medication tapering.
Resistant diseaseResistant 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) ..
RECURRENT DISEASERECURRENT DISEASE;;
scenarioscenario;Flare at more than 10 mg/day of;Flare at more than 10 mg/day of
prednisone - Disease flares at such doses ofprednisone - Disease flares at such doses of
prednisone require one of two actionsprednisone require one of two actions;;
1-Addition of a glucocorticoid-sparing1-Addition of a glucocorticoid-sparing
drug if neitherdrug if neither azathioprineazathioprine nornor
methotrexatemethotrexate has been used.has been used.
2-Treatment of the flare as a case of
resistant disease if the patient is already
taking either azathioprine or
Action, a higher dose of prednisone,
generally in the range of 1 mg/kg per day,
will be required to reestablish disease
scenarioscenario;Flare at 10 mg/day of;Flare at 10 mg/day of
prednisoneprednisone or less — If a disease flareor less — If a disease flare
occurs at a prednisone dose of 10 mg/day oroccurs at a prednisone dose of 10 mg/day or
there are two options that are USUALLYthere are two options that are USUALLY
1-Increase in1-Increase in prednisoneprednisone to the lowest doseto the lowest dose
required to reestablish disease control. Thisrequired to reestablish disease control. This
dose is based upon the severity of thedose is based upon the severity of the
patient's clinical findings. If the diseasepatient's clinical findings. If the disease
flare is detected early, the dose requiredflare is detected early, the dose required
may be significantly lower than 1 mg/kg permay 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
Once disease control is restored, slowerOnce disease control is restored, slower
tapering than was used during the initialtapering than was used during the initial
course. Some patients are maintained oncourse. Some patients are maintained on
low doselow dose prednisoneprednisone (eg, 5 mg/day) for one(eg, 5 mg/day) for one
year oryear or more.more.
scenarioscenario;Flare off prednisone but on a;Flare off prednisone but on a
glucocorticoid-sparing drugglucocorticoid-sparing drug ..
There areThere are two options in such patientstwo options in such patients;;
1-Prednisone is reinstituted at the lowest dose1-Prednisone is reinstituted at the lowest dose
required to reestablish disease control. The doserequired to reestablish disease control. The dose
selected is based upon the severity of theselected is based upon the severity of the
patient's clinical findings, and may bepatient's clinical findings, and may be
significantly lower than 1 mg/kg if the diseasesignificantly lower than 1 mg/kg if the disease
flare is detected early. The usual minimum doseflare is detected early. The usual minimum dose
is 20 mg/day.is 20 mg/day.
2-The glucocorticoid-sparing drug can be2-The glucocorticoid-sparing drug can be
changed from azathioprine tochanged from azathioprine to
methotrexate or vice versa.methotrexate or vice versa.
Multiple options exist for treating patientsMultiple options exist for treating patients
who do not respond adequately towho do not respond adequately to
glucocorticoids plus azathioprine orglucocorticoids plus azathioprine or
methotrexate. Evidence of clinicallymethotrexate. Evidence of clinically
significant benefit is greatest withsignificant benefit is greatest with
rituximab and intravenous immune globulinrituximab and intravenous immune globulin
(IVIG). Priority for using rituximab first in(IVIG). Priority for using rituximab first in
this setting, and then trying IVIG ifthis setting, and then trying IVIG if
rituximab fails.rituximab fails.
other therapies must be considered afterother therapies must be considered after
excluding myositis mimicsexcluding myositis mimics::
1- dystrophies1- dystrophies
2-Endocrinopathies eg thyroid dis.2-Endocrinopathies eg thyroid dis.
Multiple options exist for treating patients who do not
respond adequately to glucocorticoids plus either
azathioprine or methotrexate; include:
-Intravenous immune globulin (IVIG)
-Calcineurin inhibitors (Cyclosporine, Tacrolimus).
-Tumor necrosis factor inhibitors
-Combination therapy with azathioprine and
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
Predictors of improvement with rituximab included the
presence of an• anti-synthetase antibody, anti-Mi-2,
juvenile dermatomyositis and lower physician global
The trend with the use of rituximab IVI is
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.
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.
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.
IVIG is an important agent in the setting of:-
-patients with contraindications to immunosuppressants,
- refractory lung disease.
-statin-associated immune-mediated necrotizing myopathy•
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
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
Rituximab is better IVIG
The reasons for favoring rituximab over IVIG, are the
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
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.
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.
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.•
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.
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
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).
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).•
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
APPROACH TO REFRACTORY SKIN DISEASE
Therapy of cutaneous disease of DM is often difficult.
Sun avoidance and sun protective measures (for
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
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
-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
Sirolimus may also be of use in some patients.
Dalakas MC. Nat Rev Rheumatol.2010 APPROACH TO REFRACTORY SKIN
Cases of calcinosis may respond to .
low- dose warfarin ,
or electric shock wave lithotripsy However, none of
these therapies have been shown to be consistently
For patients who experience disease flares after the
achievement of disease control, there are four specific
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.)
• 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).
• 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).
• 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
• 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:
• Intravenous immune globulin (IVIG)
• Mycophenolate mofetil
• Tumor necrosis factor inhibitors
• Combination therapy with azathioprine and