Treatment of resistant & relapsing polymyositis dm

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