Idiopathic inflammatory myopathies (IIMs) are a group of rare autoimmune diseases that cause inflammation and weakness in the muscles, and can also affect other organs like the skin, lungs, and heart.

1. PHARMACOTHERAPY OF IDIOPATHIC
INFLAMMATORY MYOPATHIES
Dr. Ebenezer Kwabena Tetteh
PHMD 354: Pharmacotherapy of Musculoskeletal Disorders
Department of Pharmacy Practice and Clinical Pharmacy – UGSOP

2. OUTLINE
• Background
• Goals of pharmacotherapy
• Treatment options
• Corticosteroids
• Antimalarials (for their anti-inflammatory and immunosuppressant properties)
• Immunosuppressive agents (biologics and non-biologics)
• Treatment protocols

3. BACKGROUND
• Idiopathic inflammatory myopathies (IIM) are rare autoimmune disorders that affect more women
than men. In children, it is referred to as juvenile IIM. IIM manifests as chronic inflammation of
muscle tissue, reduced muscle strength and symmetrical proximal muscle weakness (= both sides
of the upper half of the body are affected)
• IIM is triggered by infiltration of normal, healthy muscle fibres by lymphocytes (T-cells, B-cells)
and antigen-presenting cells (e.g., macrophages, dendritic cells). In about 60% of IIM patients,
autoantibodies are produced against nuclear and cytoplasmic components of muscle and
connective tissues. It may affect organ systems (for e.g., the lungs and heart) and adults with IIM
have a higher risk of getting breast, colorectal, lung, ovarian, pancreatic or stomach cancer
• There are five subtypes:
• Dermatomyositis, which accounts for ~ 67% of cases
• Antisynthetase syndrome
• Necrotizing autoimmune myositis (NAM)
• Polymyositis
• Inclusion body myositis

4. BACKGROUND
• Dermatomyositis usually presents with symmetrical proximal muscle weakness and
photosensitive skin rashes (in a V-sign). Myositis-specific autoantibodies are present, some of
which are linked to skin rashes (lesions) or associated with cancer
• If patients have muscle weakness and no skin rash = Dermatomyositis sine dermatitis
• If patients have skin rashes with no muscle weakness = Amyopathic dermatomyositis
• Antisynthetase syndrome presents with proximal muscle weakness and myositis-specific
autoantibodies that are not found in dermatomyositis
• Necrotizing autoimmune myositis (NAM) presents with proximal muscle weakness and
myositis-specific autoantibodies plus NAM-specific autoantibodies
• Polymyositis presents with proximal muscle weakness without a skin rash and without
myositis-specific autoantibodies (other autoantibodies are however expressed)
• Inclusion body myositis presents with proximal muscle weakness but may also affect distal
muscles (i.e., affects wrist extension, forearm motion etc.)

5. GOALS OF PHARMACOTHERAPY
• The goals of pharmacotherapy in IIM include:
• Improving muscle strength (= reversing muscle weakness)
• Minimizing long-term muscle damage
• Prevention of complications from muscle weakness
• Reducing side-effects of long-term medication use
• Improvement of physical, mental and social well being

6. TREATMENT OPTIONS
• Treatment options for idiopathic inflammatory myopathies include:
• Corticosteroids
• Antimalarials
• Hydroxychloroquine
• Chloroquine
• Immunosuppressive agents
• Biologic agents, e.g., intravenous immunoglobulins (IVIG) and rituximab, a
monoclonal antibody
• Non-biologic agents, e.g., the antimetabolites azathioprine, methotrexate,
mycophenolate mofetil

7. CORTICOSTEROIDS
• Corticosteroids exert anti-inflammatory and immunosuppressive effects in IIM by non-
selectively inhibiting the expression of interleukin-2, interleukin-6, tumour-necrosis-factor
alpha and prostaglandins. They include:
• Betamethasone** (** = long-acting and more potent anti-inflammatory effects)
• Dexamethasone**
• Methylprednisolone* (* = intermediate duration of action)
• Prednisolone*
• Corticosteroids and their synthetic derivatives differ in their metabolic (glucocorticoid)
effects and electrolyte-regulating (mineralocorticoid) effects
• By virtue of their glucocorticoid properties, they act on almost every organ system. Steroid
therapy is therefore associated with a wide range of adverse systemic effects (some of which
are life-threatening). Also, treatment discontinuation is associated with adverse effects, and
sometimes reactivation of the disease being treated

8. CORTICOSTEROIDS
• Side effects of corticosteroids, esp. with long-term use, include:
• Immunosuppression: Increased susceptibility to infections, suppressed/ delayed
hypersensitivity, reduced inflammatory responses, lymphocytopenia
• Musculoskeletal disorders: Osteoporosis, osteonecrosis, bone fractures, myopathy
• Gastrointestinal: Peptic ulcers and gastrointestinal bleeding (risk of which is elevated
when co-administered with NSAIDs), pancreatitis
• Cardiovascular: Hypertension, fluid retention (oedema), accelerated atherosclerosis
• Endocrine-metabolic: Glucose intolerance, weight gain, fat redistribution (Cushing’s
syndrome), muscle wasting, impaired wound healing, impotence, irregular menses
• Dermatologic: Acne, hirsutism (excessive hair growth), skin fragility
• Neuropsychiatric: Altered mood and emotions, euphoria, insomnia, depression, psychosis
• Ophthalmologic: Cataract, glaucoma

9. CORTICOSTEROIDS
• Steroid-induced immunosuppression might interfere with the efficacy and safety of live
attenuated vaccines. It is best to avoid vaccinations using (attenuated) “live” vaccines in
patients taking more than 10 mg of prednisolone daily and/or other immunosuppressants.
Steroid interference with vaccine efficacy and safety does not seem to be an issue with
hepatitis B, influenza, pneumococcal or COVID-19 vaccines
• Cushing’s syndrome, insomnia and chronic fatigue syndrome associated with long-term
corticosteroids use are thought to be due an altered circadian rhythm. The circadian
rhythm is a biological clock, an internal time-keeping system that controls physiological
activities in the human body over a 24-hour period
• Levels of circulating (endogenous) glucocorticoids play a role in maintaining the
biological clock and to mitigate against corticosteroid-therapy-induced alternations of the
circadian clock, immediate release formulations of corticosteroids should be administered
in the morning to coincide with the circadian rhythm

10. CORTICOSTEROIDS
• To prevent steroid-withdrawal effects and avoid adverse systemic effects from long-term
use (for e.g., if patients are to given steroid therapy for 9-12 months), initial oral doses
should be slowly tapered after 4-8 weeks. After 1-2 months, an initial steroid dose, of say
1 mg kg-1
day-1
, should be given on alternate days OR reduced by 20-25% each month
until a daily dose of 5-10 mg is reached at which point tapering is stopped
• Corticosteroid-induced osteoporosis or fractures (due to a decline in bone mineral density
and bone mass) can be reduced by using bisphosphonates (e.g. pamidronate, alendronate)
or calcium plus vitamin D supplements. Also, gastrointestinal bleeding and ulcers can be
resolved using H2 antagonists or proton-pump inhibitors (PPIs). Clinical evidence
supports use of PPIs, e.g. omeprazole, esomeprazole
• It is expected that about 50% of IIM patients may fail to respond to steroid therapy; in
which case tapering should be accelerated in order to start treatment with other agents
early. There is also the possibility of steroid-induced myopathy = availability of steroid-
sparing therapy is crucial even if patients respond to corticosteroid therapy

11. ANTIMALARIALS
• Antimalarials used in IIM are mostly chloroquine and hydroxychloroquine
• The antimalarials have immunosuppressive and anti-inflammatory properties, besides their
antimalarial activity against erythrocytic forms of the parasite Plasmodium
• Hydroxychloroquine is the preferred antimalarial due to a reduced likelihood of adverse ocular
and gastrointestinal effects relative to chloroquine. It is considered safe for use in pregnancy.
Its slow-onset of action makes it suited for long-term treatment of chronic disease
• Chloroquine and hydroxychloroquine accumulate in skin tissue (and probably any
melanin-containing tissue) and hence thought to be good for cutaneous manifestations of
IIM disease, for e.g., (amyopathic) dermatomyositis
• The antimalarials are frequently used in combination with corticosteroids to reduce the need
for high-dose steroid therapy or lengthy steroid treatment. The antimalarials are steroid-sparing
agents

12. ANTIMALARIALS
• Side effects of long-term use of antimalarials include:
• Nauseas and epigastric burning (stomach upset) = antimalarials should be taken with food
• CNS effects e.g., headache, dizziness, nervousness, insomnia
• Skin rashes, dermatitis and skin pigment changes
• Irreversible retinal toxicity. Rare with hydroxychloroquine but it is advisable for patients
to wear sunglasses in sunlight
• Corneal deposits that are reversible with treatment discontinuation
• Baseline ophthalmologic review (eye examinations) is necessary for those with pre-existing
eye disease. There should also be regular ophthalmologic monitoring thereafter (every 3
months when chloroquine is used, every 6-12 months when hydroxychloroquine is used)

13. IMMUNOSUPPRESSIVE AGENTS
• Non-biologic immunosuppressive agents are mostly antimetabolites that disrupt normal
cell functioning = cytotoxic
• Methotrexate (MTX) and azathioprine are considered first choice treatments in the class of
steroid-sparing IIM therapies. MTX and azathioprine are also first choice treatments in
situations of steroid resistance
• Azathioprine is a pro-drug that is metabolized in the gut to 6-mercaptopurine, which
interferes with purine synthesis. It is safe in pregnancy as foetal liver cannot metabolize
the drug into its active form
• Methotrexate (MTX) is a folic acid antagonist (an antifolate) that acts by inhibiting the
enzyme dihydrofolic reductase, thereby interfering with DNA synthesis. Lower doses of
MTX (than that used in cancer treatment) are used for autoimmune diseases
• Mycophenolate mofetil is also a prodrug that acts by inhibiting inosine monophosphate
dehydrogenase in purine biosynthesis. It is converted to mycophenolic acid in the body,
which restrains T and B cell proliferation. It is less toxic than azathioprine

14. IMMUNOSUPPRESSIVE AGENTS
• Side effects of non-biologic immunosuppressive agents
• Use of MTX is associated with mouth sores, stomach upset, infections, hepatorenal
toxicity and leukopenia. It is also associated with pulmonary toxicity (pneumonitis) and
must be used with caution in IIM patients with lung disease. A dry non-productive cough
following MTX use is a sign of lung toxicity
• Azathioprine or mycophenolate mofetil are better choices for IIM patients with lung
disease. Both azathioprine and mycophenolate mofetil are however associated with
myelosuppression, hepatotoxicity, lymphatic disorders and infections
• NB: Non-biologic (chemically-synthesized) immunosuppressive agents are cytotoxic and this
is not an exhaustive list of their side effects. You should read more about these side effects

15. IMMUNOSUPPRESSIVE AGENTS
• Biologic immunosuppressive agents used in IIM include: intravenous immunoglobulin (IVIG)
and rituximab, a monoclonal antibody. The name extension “–mab” = monoclonal antibody
• IVIG is used as rescue or salvage therapy in patients with rapidly progressive IIM disease who
cannot tolerate, or have poor response to corticosteroid therapy. IVIG has multiple
mechanisms of action that include downregulating the activity of proinflammatory cytokines
and neutralizing the action of circulating (myositis-specific) autoantibodies
• IVIG doesn’t seem to be effective in inclusion body myositis, but for a short period of time, it
works for those with dysphagia (i.e., have difficulty swallowing) or oropharyngeal dysfunction
• Rituximab, given as an infusion, is indicated for IIM that is refractory to first-line therapy
with corticosteroids and at least one steroid-sparing agent. It binds to a protein (receptor,
antigen) called CD20 found on the surface of B-cell lymphocytes, resulting in anti-
proliferative effects and depletion of B-cells. B-cell recovery starts after completion of
rituximab treatment

16. IMMUNOSUPPRESSIVE AGENTS
• Side effects of biologic immunosuppressive agents
• Common side effects of IVIG, for e.g., flu-like symptoms (headache, fever, chills),
fatigue are mild and transient. Other rare adverse events, e.g., arrhythmias, renal
impairment, transfusion-related acute lung injury are serious
• Slowing down infusion rate, premedication with steroids and antihistamines, and
switching to subcutaneous formulations of IG are thought to reduce severity and
incidence of these adverse effects
• Infusion of rituximab is associated with allergic reactions, that can also be mitigated by
premedication with methylprednisolone and/or antihistamines (= diphenhydramine or
equivalent). Bacterial and viral infections have been reported but these respond well to
antibacterial and antiviral treatment

17. TREATMENT PROTOCOLS
Treatment of mild conditions. Treatment protocol based on evidence rated [B]
• Prednisolone, oral 0.5-1 mg per kg body weight daily (not to exceed 80 mg daily) AND
• Omeprazole, oral 20 mg daily OR esomeprazole, oral 20-40 mg daily; AND
• Calcium supplements with vitamin D as required OR bisphosphonates**
Treatment of rash in dermatomyositis
• Prednisolone, oral 0.5-1 mg per kg body weight daily (not to exceed 80 mg daily); AND
• Omeprazole, oral 20 mg daily OR esomeprazole, oral 20-40 mg daily; AND
• Calcium supplements with vitamin D as required OR bisphosphonates**; AND
• Hydroxychloroquine, oral 200-400 mg daily
• ** Use of bisphosphonates e.g., pamidronate, alendronate require consultation with a specialist

18. TREATMENT PROTOCOLS
Treatment in cases of steroid resistance. Treatment protocol based on evidence rated [B]
• Methotrexate, consult a specialist; OR
• Azathioprine, consult a specialist; OR
• Mycophenolate mofetil, consult a specialist; OR
• Intravenous immunoglobulin (IVIG), consult a specialist; OR
• Rituximab, consult a specialist
• NB: Tumour necrosis factor alpha inhibitors (infliximab, adalimumab, etanercept) are not
effective in IIM and may worsen the disease. Also, the antimetabolites (with or without
corticosteroids) are not as effective as IVIG in inclusion body myositis. Aggressive treatment
of IIM and its subtypes may therefore use combinations of the drugs above and corticosteroids

19. CLASS DISCUSSION:
WHAT IS THE RATIONALE FOR THESE TREATMENT
PROTOCOLS?

20. KEY MESSAGES
• Idiopathic inflammatory myopathies are rare autoimmune diseases that often affect muscle
tissues in the proximal (upper) regions of the body. Muscle inflammation and weakness is
symmetrical, i.e., affects both left and right sides of upper half of the body
• There are five subtypes of IIM: (i) dermatomyositis, (ii) antisynthetase syndrome, (iii)
necrotizing autoimmune myositis, (iv) polymyositis, and (v) inclusion body myositis
• Treatment options for IIM include:
• Corticosteroids
• Antimalarials (for their anti-inflammatory and immunosuppressant properties)
• Immunosuppressive agents (biologics and non-biologics)
• In the past, treatment of IIM relied mostly on corticosteroids but use of steroid-sparing
immunosuppressive agents has grown in recent times

21. QUESTIONS