For post graduates and physicians interested in Rheumatology Immunology.

1. RESISTANT & RELAPSING POLYMYOSITIS
Prof. Abd El Azeim Alhefny
Professor of Internal Medicine
Director of Rheumatology Unit
Ain Shams University

2. 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.

3. activation of the endoplasmic reticulum stress response, and cleavage of autoantigens

4. Heliotrope Rash
Violaceous erythematous rash with or without edema in a symmetrical distribution involving periorbital skin. +/- Facial erythema

5. Gottron Papules
slightly elevated violaceous papules and plaques over bony prominences, particularly the MCP, PIP, and/or DIP. +/- the elbows, knees, feet.

6. Heliotrope & Gottron

7. Nailfold changes consist of periungual telangiectases (+ capillary microscopy) and/or hypertrophy of the cuticle and small hemorrhagic infarcts.
Periungual Telangiectases

8. Fissured, scaly, hyperkeratotic & hyperpigmented hands are suggestive of manual labor.
Mechanic's hand

9. 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).

10. Calcinosis Cutis
•Firm, yellow- or flesh-colored nodules, often over bony prominences.
•Nodules may ulcerate with secondary infection

11. 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

12. 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

13. 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.

14. 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.

15. Biopsy: Chronic inflammatory infiltrate of CD8+ T lymphocytes in PM (usually from deltoid, triceps or biceps).

16. EMG
Short-duration, low- voltage, polyphasic motor unit action potentials with spontaneous fibrillation activity

17. 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

18. 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:

19. 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.

20. 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

22. 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

24. 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

25. RESISTANT/REFRACTORY
POLYMYOSITIS

26. 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

28. ACTH gel was given as an 80U (1ml) subcutaneous injection once or twice weekly over 12 weeks for short-course treatment of exacerbations.

29. 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

30. 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.

31. 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

32. 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.

33. 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.

35. 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.

36. 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

38. 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

40. 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.

41. Evidence of clinically significant benefit is greatest with rituximab and IVIG if rituximab fails.
Arthritis Rheum 2013
Rituximab & IVIG

42. 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.

44. Conclusion:

46. 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

47. 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.

48. 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).

50. 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).

52. 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.

53. RELAPSING POLYMYOSITIS

54. 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….

55. 1st Scenario
disease flares at > 10 mg/day prednisone
(if not MTX or
AZAalready used)
a higher dose 1 , prednisone ofmg/kg per day, will be required to reestablish disease control
If no improvement treatment of the patient as a case of resistant disease

56. 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 theif this has not been maximized already
Once disease control is restored, slower steroid tapering than that which was used during the initial course.

57. 3rd Scenario
disease flares but prednisone offon a glucocorticoid- sparing drug
reinstituting prednisone at the lowest dose required to reestablish disease control
changing the glucocorticoid-sparing medication or MTX to AZA fromvice versa
If the patient has already failed both AZA and MTX, treat as a case of resistant disease

58. 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.

59. 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

60. 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

61. 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

62. REMEMBER

63. 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

64. 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.

66. 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.

67. 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