treatment of resistant & relapsing polymyositis dm
DESCRIPTION
For post graduates and physicians interested in Rheumatology Immunology.TRANSCRIPT
RESISTANT &
RELAPSING
POLYMYOSITIS
Prof. Abd El Azeim Alhefny
Professor of Internal Medicine
Director of Rheumatology Unit
Ain Shams University
IDIOPATHIC INFLAMMATORY
MYOPATHIES
IIM is a heterogeneous group of disorders
characterized by chronic inflammation of striated
muscles and skin.
Painless Symmetrical proximal muscle weakness
with characteristic skin rash is the hallmark feature.
Increased serum muscle enzymes, muscle biopsy,
EMG, and MRI changes can assist in the diagnosis.
activation of the endoplasmic reticulum stress
response, and cleavage of autoantigens
Heliotrope Rash
Violaceous erythematous rash with or without edema in a symmetrical distribution
involving periorbital skin. +/- Facial erythema
Gottron Papules
slightly elevated violaceous papules and plaques over bony prominences,
particularly the MCP, PIP, and/or DIP. +/- the elbows, knees, feet.
Heliotrope & Gottron
Nailfold changes
consist of periungual
telangiectases (+
capillary microscopy)
and/or hypertrophy of
the cuticle and small
hemorrhagic infarcts.
Periungual Telangiectases
Fissured, scaly,
hyperkeratotic &
hyperpigmented
hands are
suggestive of
manual labor.
Mechanic's hand
Shawl sign
Poikiloderma may occur on exposed skin, such as the extensor surfaces of the arm, and may appear in a V-shaped distribution over the anterior neck and upper chest and back (ie, shawl sign).
Calcinosis Cutis
• Firm, yellow- or flesh-colored
nodules, often over bony
prominences.
• Nodules may ulcerate with secondary
infection
46 year old female with
DM and extensive soft
tissue calcifications
about the
knee and hip.
The use of the calcium channel
blocker diltiazem (240 mg bid) leades
to gradual resolution of calcinosis.
Extensive Soft Tissue Calcifications
ILD
May vary from asymptomatic to
severe, rapidly progressive
dyspnea with pulmonary
insufficiency and fatal outcome.
Clinically there is bibasilar
crepitations
PFTs: restrictive pattern, ↓DLCO
AutoAbs to Jo-1 (in 50-
100% correlate with ILD:
Low CK associated with
more severe ILD
Laboratory Workup
CPK levels are often abnormal, except in patients with amyopathic DM.
The most sensitive/specific enzyme is elevated creatine kinase (CK), & aldolase
, AST, LDH.
At times, the elevation of the enzymes precedes clinical evidence of myositis.
Several serologic abnormalities in 30% {myositis-specific antibodies (MSAs)}.
A positive ANA finding is common in patients with DM.
Anti–Jo-1 (antihistidyl transfer RNA [t-RNA] synthetase) PM>DM. It is
associated with pulmonary involvement (ILD), RP, arthritis, and mechanic's
hands.
Other MSAs include anti-signal recognition protein (anti-SRP), associated
with severe polymyositis, and anti–PM-Scl and anti-Ku, with PM/SCL overlap
Anti–Mi-2 antibodies are highly specific for DM but lack sensitivity (25%).
They are associated with acute-onset classic DM with shawl rash and a
relatively good prognosis.
MRI of thighs showing increased signal in the quadriceps
muscles bilaterally consistent with inflammatory myositis
. • MRI is useful in differentiating steroid myopathy from continued
inflammation.
• MRI may serve as a guide in selecting a muscle biopsy site.
Biopsy: Chronic inflammatory infiltrate of
CD8+ T lymphocytes in PM (usually from deltoid, triceps or
biceps).
EMG
Short-duration, low-
voltage, polyphasic
motor unit action
potentials with
spontaneous
fibrillation activity
Prognosis
5-year survival rates have been estimated >80%.
Mortality is most often related to associated malignancy
or cardio-pulmonary complications.
Polymyositis usually responds well to treatment but
residual weakness occurs in about 30% of patients.
5% of DM patients have a fulminant progressive course
with eventual death.
Pappu R et al; Polymyositis, Medscape, Sep 2011
Older age, female sex.
Interstitial lung disease, cardio-pulmonary
involvement, associated malignancy.
Presence of anti-Jo-1 (lung disease) and anti-Signal
Recognition Protein antibodies (severe muscle disease,
cardiac involvement). Persistently high CK
Delayed or inadequate treatment.
Dysphagia, dysphonia.
Callen JP; Dermatomyositis, Medscape, Oct 2012
Poor prognostic factors:
Rule out underlying malignancy
PM and especially DM may be part of a
paraneoplastic syndrome.
10 - 20% of patients with DM have neoplasms;…
more in elderly patients.
Breast cancer, lung cancer, ovarian
carcinoma and gastric carcinoma are usually
implicated.
Nonpharmacologic
Sun-blocking agents should be used.
Encourage physical activity to maintain muscular strength.
Evaluation of swallowing and a speech and language therapist may help.
Monitor CPK and clinical response.
Treatment
Early initiation of therapy is essential.
Steroids are the most important drugs.
In mild disease, topical steroids is effective. In more severe
disease, high doses of systemic steroids are used then tapered.
Improvement is usually apparent by the second or third month.
If steroids fail then azathioprine or methotrexate can be used.
Other treatments include antimalarial agents and
immunomodulatory therapies.
Patients with anti-Jo-1 antibodies need long-term
immunosuppression.
For lung disease, an aggressive combination regimen including
ciclosporin A or tacrolimus with cyclophosphamide is
recommended to be added to corticosteroids.
Treatment
Most patients respond to initial therapy, and some
achieve sustained disease control either off all
therapy or with low-dose maintenance therapy.
But many patients require intermittent or even
continuous therapy…..
Treatment
RESISTANT/REFRACTORY
POLYMYOSITIS
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)
other therapies must be considered after excluding myositis mimics:-
dystrophies,
Endocrinopathies eg thyroid dis.,
as well as malignancy
http://www.rheumatologynetwork.com/myositis/refractory-myositis
ACTH gel was given as an 80U (1ml) subcutaneous injection once or twice weekly over 12
weeks for short-course treatment of exacerbations.
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
RESISTANT DISEASE
Rituximab
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.
The trend with the use of rituximab IVI is either:-
two 1 gram doses one week apart.
1g on Day 0 and Day 14 (used in RIM study), or
375 mg/m2 BSA once weekly times four doses.
Rituximab
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, with consideration for a different trial design.
In conclusion,
Oddis et al have proved that large treatment trials are possible in this difficult
disease.
Future trials will benefit from the experience obtained in the RIM Study.
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.
It 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.
Polymyositis and dermatomyositis. 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 Immunoglobulin
Rituximab is better IVIG
The reasons for favoring rituximab over IVIG, are
the following:
Rituximab appears to be effective in CTD resembling
DM and PM, such as SLE and RA.
If effective, rituximab may be more likely to lead to
a prolonged period of disease control.
Many patients who respond to IVIG require
continued treatments on a monthly basis.
Evidence of clinically significant benefit is
greatest with rituximab and IVIG if
rituximab fails.
Arthritis Rheum 2013
Rituximab & IVIG
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.
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.
TACROLIMUS
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.
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).
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 adverse effects.
RELAPSING POLYMYOSITIS
RELAPSING DISEASE
After achieving disease control with treatment,
some patients experience disease flares during or
after the period of medication tapering.
For those patients who experience recurrent
disease, there are four specific scenarios….
1st Scenario
disease flares at > 10 mg/day prednisone
(if not MTX or AZAalready used)
a higher dose
1 , prednisone of
mg/kg per day, will
be required to
reestablish disease
control
If no improvement treatment of the
patient as a case of resistant disease
2nd Scenario
disease flares at mg/day 10 <
prednisone of
increasing the prednisone to the lowest dose required
to reestablish disease control (20mg-1mg/kg/day)
increasing dose, MTX or AZA the
if this has not been maximized already
Once disease control
is restored, slower
steroid tapering than
that which was used
during the initial
course.
3rd Scenario
disease flares but prednisone off
on a glucocorticoid-sparing drug
reinstituting
prednisone at the
lowest dose required to
reestablish disease
control
changing the glucocorticoid-sparing
medication or MTX to AZA from
vice versa
If the patient has
already failed both
AZA and MTX,
treat as a case of
resistant disease
4th Scenario
disease flare off all immunosuppressive
medication
prednisone reinstituting with an initial daily
dose that varies according to relapse
mg/d)20 >severity (
a glucocorticoid-
sparing drug should
be resumed or
started.
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
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, when all
other measures fail.
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
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 effective for
calcinosis secondary to DM.
Resolution of calcinosis has also been
reported in patients receiving treatment for
DM with infliximab , IVIG, or hematopoietic
stem cell transplantation .
• Surgical excision can be used to remove cutaneous or subcutaneous lesions that
are unresponsive to medical therapy. Arthritis Rheum. 2005
REMEMBER
Take Home Massage
Treatment decisions are typically empirically based; due to few controlled
trials and a lack of targeted immunosuppression.
Expert consensus supports high-dose oral prednisone as first-line therapy;
however, as many as 30%–40% of patients may fail to respond, and up to
40% or more experience major adverse events with long-term steroid use.
Steroid-sparing or alternative immunosuppressive therapies, including MTX,
AZA, cyclosporine, and MMF, should be added.
IVIG is considered a second-line therapy for DM, but not for PM. However it
does not have a US FDA indication for myositis, and is very expensive with
a risk of acute renal failure.
Rituximab had shown some promise in many case series.
Clearly, additional effective and tolerable treatment options are needed.
Clin Nephrol. 2011
REFERENCES
Noss EH, Hausner-Sypek DL, Weinblatt ME. Rituximab as therapy for refractory polymyositis and dermatomyositis. J
Rheumatol 2006; 33:1021.
Mahler EA, Blom M, Voermans NC, et al. Rituximab treatment in patients with refractory inflammatory myopathies.
Rheumatology (Oxford) 2011; 50:2206.
Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guideline: intravenous immunoglobulin in the treatment of
neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American
Academy of Neurology. Neurology 2012; 78:1009.
Cherin P, Pelletier S, Teixeira A, et al. Results and long-term followup of intravenous immunoglobulin infusions in
chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum 2002; 46:467.
Qushmaq KA, Chalmers A, Esdaile JM. Cyclosporin A in the treatment of refractory adult
polymyositis/dermatomyositis: population based experience in 6 patients and literature review. J Rheumatol 2000;
27:2855.
Ochi S, Nanki T, Takada K, et al. Favorable outcomes with tacrolimus in two patients with refractory interstitial lung
disease associated with polymyositis/dermatomyositis. Clin Exp Rheumatol 2005; 23:707.
Rowin J, Amato AA, Deisher N, et al. Mycophenolate mofetil in dermatomyositis: is it safe? Neurology 2006; 66:1245.
Pisoni CN, Cuadrado MJ, Khamashta MA, et al. Mycophenolate mofetil treatment in resistant myositis. Rheumatology
(Oxford) 2007; 46:516.
Sinoway PA, Callen JP. Chlorambucil. An effective corticosteroid-sparing agent for patients with recalcitrant
dermatomyositis. Arthritis Rheum 1993; 36:319.
Yamasaki Y, Yamada H, Yamasaki M, et al. Intravenous cyclophosphamide therapy for progressive interstitial
pneumonia in patients with polymyositis/dermatomyositis. Rheumatology (Oxford) 2007; 46:124.
Muscle Study Group. A randomized, pilot trial of etanercept in dermatomyositis. Ann Neurol 2011; 70:427.
Anandacoomarasamy A, Howe G, Manolios N. Advanced refractory polymyositis responding to infliximab.
Rheumatology (Oxford) 2005; 44:562.
Efthimiou P, Schwartzman S, Kagen LJ. Possible role for tumour necrosis factor inhibitors in the treatment of resistant
dermatomyositis and polymyositis: a retrospective study of eight patients. Ann Rheum Dis 2006; 65:1233.
ACTH gel
This is the long-acting formulation of the full-sequence ACTH including pro-opiomelanocortin peptides. Its action appears to involve more than steroidogenesis, with anti-inflammatory and immunomodulatory effects exerted through the melanocortin system.12
Originally approved by the FDA for treatment of myositis in 1952, its renewed FDA approval in 2010 has brought a resurgence of interest in ACTH gel.
However, the clinical data are limited. A small retrospective case series showed clinical improvement in weakness and rash in 3 patients with dermatomyositis and 2 with polymyositis refractory to steroids and multiple other immunosuppressants.13
ACTH gel was given as an 80U (1ml) subcutaneous injection once or twice weekly over 12 weeks for short-course treatment of exacerbations.
CYCLOSPORINE
Efficacy for cyclosporine has been suggested for both primary
therapy and resistant disease, including ILD.
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/day.
Over the median six month course of treatment with
cyclosporine, the daily prednisone dose was reduced by 75%.
All the patients demonstrated improved strength in the
shoulder girdle; 4 patients had stronger hip flexor muscles.
BMC Musculoskelet Disord. (2012) 13:228