Myositides
The idiopathic inflammatory myopathies (IIMs) encompass a group of heterogeneous muscle
disorders that share the clinical features of slowly progressive weakness of skeletal muscle,
decreased muscle endurance and muscle fatigue, with presence of inflammatory infiltrates
(mainly composed of T cells, macrophages, DCs, B cells, plasma cells and eosinophils) in
muscle tissue and positive autoantibodies.
Most commonly, we classify as dermatomyositis (DM), anti-synthetase syndrome
(ASyS), immune-mediated necrotizing myopathy (IMNM) and inclusion body myositis (IBM).
All other cases are classified as polymyositis (PM).
Muscle physiology
Each muscle fiber is surrounded by the endomysium. Several fibers form a fasciculus,
surrounded by the perimysium. Several fascicles form the muscle, surrounded by epimysium
(a fascia).The specificity of fiber type in a muscle is established during development in the
embryonic muscle and seems to be genetically determined.
-type I fibers: slow-twitch, characterized by a relatively low ATPase reactivity and
large and numerous mitochondria, which makes them fatigue resistant and suitable for
prolonged aerobic exercise and endurance work.
-type II fibers (IIA, IIB): fast-twitch, have a high ATPase activity, rely mainly on
glycolytic systems for energy supply and are important for quick, powerful actions.
-type IIC: intermediate, undifferentiated transition fibers that can develop into
either type I or type II fibers.
Each muscle is composed of a mixture of type I and II fibers. Marathon runners
have a predominance of slow-twitch (type I), while sprinters have more fast-twitch (type II).
The phenotype of a developing muscle fiber differs from that of mature muscle
fibers in the expression of molecules on the cell surface or in the cytoplasm. One
characteristic phenotype of mature, differentiated muscle fibers is absence of MHC-I.
Muscle has a regenerating capacity depending on satellite cells, stem cells localized
under the basal lamina of the muscle fiber. Similar to myotubes (immature muscle fibers),
regenerating fibers express MHC-I on the sarcolemma and in the sarcoplasm.
Epidemiology
♀:♂= 2.5:1, for overlap 10:1, jDM 1:1 and IBM mostly in men. IIM has a 3-4:1 Black/White
ratio of incidence and a younger adult onset peak in Blacks. Incidence: 1-20/million per year,
prevalence 5-22/million. Peak age of onset is bimodal in distribution for DM: one peak at 5-
15yrs and the other at 45-65yrs. PM rarely occurs in patients <15yrs, with mean age of onset
50-60yrs. Geographical gradient north to south, most in equator (UV radiation?).
Causes
-Environmental: UV-radiation (Mi2), drugs (statins, GCs, immune-checkpoint inhibitors).
-Infectious: Coxsackie (jDM), flu, HIV, HSV and other viral
-Smoking
-Genetics: HLA-II (HLA DRB1*0301, DQA1*0501), PTPN22 (TCR signaling), IL-1, TNF.
-GVHD
Criteria
several limitations, including the inability to identify key clinical subsets such as IMNM and
CADM and the lack of inclusion of defined MSAs beyond anti-Jo-1 (back in 2017, other Abs
were not known).
,Clinical
Most common is insidious, progressive and painless symmetric proximal muscle weakness
(pain = IMNM or even PMR?) arising over the course of 3-6 months. jDM has a more acute
onset of disease, with fever, muscle pain and weakness developing in several weeks.
Fatigue is a prominent complaint in patients with IIM and fever is observed in jDM
and adults with ASyS. Weight loss may occur as in any systemic inflammatory disorder, but if
persistent and severe, associated malignancy should be considered.
Most patients fall into one of three categories: i) with only muscular symptoms, ii)
with only extramuscular symptoms (skin, ILD, arthritis), iii) with both (DM).
Overlaps
might affect more distal than proximal muscles + head drop
-with SSc: Raynaud, puffy fingers, sclerodactyly, distal esophageal dysmotility
-with SLE: photosensitivity, malar rash, alopecia, polyarthralgia, pleuritis, leukopenia
Skeletal muscle
The onset of muscle weakness is typically insidious, bilateral, symmetric and painless, with
involvement of proximal more than distal muscles, with weakness being disproportionally
greater than atrophy. An exception is IBM, in which asymmetric distal weakness and atrophy
are as prominent as the proximal muscle findings. Pelvic girdle is often affected initially
(while for PMR shoulders are a necessary criterion). Muscle pain may occur and is more
common in DM and IMNM, particularly with exercise. Ocular or facial muscle weakness is
very uncommon (consider other diagnosis), except for IBM. There can be ‘head drop’
because the neck flexor muscles are involved more than the extensors. Muscle atrophy and
joint contractures are late findings in chronic PM/DM, in contrast to IBM where muscle
atrophy is more common at initial evaluation.
Pharyngeal muscle weakness may contribute to dysphagia, hoarseness, nasal
regurgitation of liquids or aspiration pneumonia. Respiratory muscle weakness may
contribute to dyspnea, although ILD is a more common cause of pulmonary dysfunction.
Clues of non-immune-mediated myositides: involvement of facial muscles
(including oculomotor), asymmetry (exception IBM), winged scapula, slow progression,
fasciculations, exertional weakness, no response to GCs.
*One of the most common causes of myalgia is intermittent claudication.
Skin
Precedes, develops simultaneously with or follow the muscle symptoms. In DM skin
manifestations may precede in 30%.
•DM: Gottron’s papules (60-80%) and heliotrope rash (<50%) (can be pruritic) are
pathognomonic, Gottron’s sign (a macular erythema over other extensor areas such as the
elbows, knees and ankles), cutaneous photosensitivity, “V” sign, shawl sign, holster sign,
cuticular hypertrophy and hemorrhage with periungual erythema, calcinosis cutis,
telangiectasias, nailfold infarcts and capillary dilation. Later, the affected skin lesions may
become shiny, atrophic and hypopigmented with telangiectasias. DM often presents with
intensely pruritic areas of confluent, violaceous erythema on the scalp, face, upper trunk
and upper extremities and its presence differentiates DM from SLE, in which pruritus is
uncommon (heliotrope rash can be pruritic). Panniculitis presenting as erythematous,
tender, subcutaneous nodules on the lower or upper extremities is a rare manifestation.
•ASyS: “mechanic’s hands”
•MDA-5: skin and oral ulceration are characteristic.
•TIF-1γ: palmar hyperkeratotic papules, PsO-like lesions, "red-on-white" patches and
the ovoid palatal patch.
, •SAE: angel-wings
Calcinosis
More in jDM (especially black children), the younger the age the more serious and
associated with NXP2. In adults, chronic, active disease or with a delay in initial treatment.
Calcinosis may be intracutaneous, subcutaneous, fascial or intramuscular in location, with a
predilection for sites of repeated microtrauma.
Joints
Polyarthralgia and polyarthritis, if they occur, appear early in the course of disease. The
distribution is RA-like and generally mild. ASyS has higher incidence of arthritis and can be RF
(+). Joint findings are more common with overlap and ASyS, in which case they can be
chronic and deforming with instability of the interphalangeal thumb joint (“floppy thumb”
sign), erosions and periarticular calcifications.
Lung
ILD
The lung is the most common internal organ affected in PM/DM (20-80%), occurring also in
ASyS and overlap, while MDA-5 leads to RP-ILD. Dyspnea in patients with myositis has many
potential causes, including parenchymal and non-parenchymal problems such as respiratory
(diaphragmatic and intercostal) muscle weakness or cardiac dysfunction. However,
respiratory muscle weakness leading to respiratory failure or significant dyspnea is
uncommon (<5%). ILD is less common in patients with IIM associated with malignancy. Krebs
von den Lungen-6 (KL-6) [a glycoprotein localized on the membrane of type II alveolar
epithelial cells, mainly released by propagating or damaged type II alveolar epithelial cells,
and is specific for determining damage to these cells] is a useful biomarker reflecting disease
activity in various ILDs. For ASyS, ILD is more commonly seen in non-anti-Jo-1, whereas
myositis and arthritis were more in anti-Jo-1 patients.
The majority of patients with DM/PM who develop ILD have histopathologic and
radiographic patterns of NSIP or OP, who can also be present concomitantly. NSIP and OP
represent a more favorable histopathology, whereas UIP and DAD portend a more ominous
course. DM-ILD may be more commonly associated with DAD, thus indicating that
pulmonary histologic differences and CT findings may further distinguish PM from DM. In
addition, the concomitant finding of anti-Ro in patients with ASyS autoAbs may be
associated with more severe and progressive ILD.
Risk factors for ILD:
-clinical: ASyS, CADM
-lab: ASyS autoAbs, anti-MDA-5, Ro52
Screen for ILD: all IIM, except IBM. Follow-up with PFTs every 3−6months
during the first year and every 6−12 months thereafter, but CT every 3-6 months if RP-ILD,
otherwise annually.
PAH: as a result of hypoxemia-induced pulmonary vasoconstriction.
Diffuse alveolar hemorrhage with pulmonary capillaritis is uncommon but can be lethal.
Pneumomediastinum: associated with RP-ILD in the setting of CADM.
-CT: ground-glass (98–100%), reticular opacities (67–87%) and consolidations.
Honeycombing is rare.
-PFTs: restrictive and ↓ DLco.
Heart
, myocarditis, conduction abnormalities, arrhythmia. Symptomatic cardiac disease, such as
congestive heart failure, is less common, however, patients are also at increased risk for
myocardial infarction. SRP-IMNM is associated with cardiomyopathy.
Gastro
Dysphagia, regurgitation. Esophageal dysmotility is seen in both overlap disorders and pure
PM/DM. GI mucosal ulceration and hemorrhage as a result of vasculitis can occur in jDM.
NXP2 is associated with GI involvement (abdominal pain, melena and intestinal perforation).
Dysphagia may be caused by muscle weakness in the pharyngeal muscles or upper portion
of esophagus. Both upper and lower esophageal sphincters can be affected.
MCTD, SSc: only lower sphincter affected, while RA, IIM both.
-Dysphagia Dx: myasthenia Gravis, motor neuron disease, oculopharyngeal muscular
dystrophy, toxic myopathy, other IIMs, GVHD.
Vasculitic
Raynaud is most common in ASyS and SSc-overlap but is observed in all myositis subsets
except for malignancy associated myositis. The inflammatory vascular lesions of DM include
tender dermal and subcutaneous nodules, periungual infarcts and digital ulcerations.
Systemic vasculitis is common in jDM but uncommon in adults.
Renal
Renal disease is usually secondary to rhabdomyolysis. The presence of primary renal disease
should prompt a search for an associated CTD.
Subtypes
DM
nuclear origin: Mi2, TIF-1, NXP2, SAE
cytoplasmic origin: MDA-5
CADM
10-30%of DM cases. Patients are considered to have provisional CADM at 6 months and
confirmed CADM at 2 years. Perhaps >50% will develop muscle disease over time, but a
significant proportion will manifest skin-limited disease only (SAE). This form can be
associated with malignancy (TIF-1γ, NXP2), whereas other patients may develop
extramuscular manifestations such as RP-ILD (MDA-5) even in the absence of myositis. The
most associated MSA for CADM is MDA-5. A subset of patients, those with "hypomyopathic
dermatomyositis", will have minimal elevations of muscle enzymes or subtle abnormalities
on muscle studies in the absence of any objective or subjective weakness.
DM sine dermatitis
rarely patients can present with an IIM that on biopsy looks like DM (perivascular
inflammation with perifascicular atrophy) but have no skin manifestations of DM.
Association with NXP2, but can have other MSAs too.
ASyS
♀:♂=2/1, proximal muscle weakness is typically the first manifestation. ↑ CPK 5-10x. Most
patients have myositis (80%), ILD (66%) [NSIP ± OP > UIP, usually involving the lower lobes],
seronegative arthritis (60%), Raynaud (40%), rash (30%) and fever (25%). Mechanic’s hand
and hiker’s feet. Some may have DM-like rash with heliotrope or Gottron’s papules and no
mechanic’s hands. Rare association with cancer in older patients. Nailfold capillary
The idiopathic inflammatory myopathies (IIMs) encompass a group of heterogeneous muscle
disorders that share the clinical features of slowly progressive weakness of skeletal muscle,
decreased muscle endurance and muscle fatigue, with presence of inflammatory infiltrates
(mainly composed of T cells, macrophages, DCs, B cells, plasma cells and eosinophils) in
muscle tissue and positive autoantibodies.
Most commonly, we classify as dermatomyositis (DM), anti-synthetase syndrome
(ASyS), immune-mediated necrotizing myopathy (IMNM) and inclusion body myositis (IBM).
All other cases are classified as polymyositis (PM).
Muscle physiology
Each muscle fiber is surrounded by the endomysium. Several fibers form a fasciculus,
surrounded by the perimysium. Several fascicles form the muscle, surrounded by epimysium
(a fascia).The specificity of fiber type in a muscle is established during development in the
embryonic muscle and seems to be genetically determined.
-type I fibers: slow-twitch, characterized by a relatively low ATPase reactivity and
large and numerous mitochondria, which makes them fatigue resistant and suitable for
prolonged aerobic exercise and endurance work.
-type II fibers (IIA, IIB): fast-twitch, have a high ATPase activity, rely mainly on
glycolytic systems for energy supply and are important for quick, powerful actions.
-type IIC: intermediate, undifferentiated transition fibers that can develop into
either type I or type II fibers.
Each muscle is composed of a mixture of type I and II fibers. Marathon runners
have a predominance of slow-twitch (type I), while sprinters have more fast-twitch (type II).
The phenotype of a developing muscle fiber differs from that of mature muscle
fibers in the expression of molecules on the cell surface or in the cytoplasm. One
characteristic phenotype of mature, differentiated muscle fibers is absence of MHC-I.
Muscle has a regenerating capacity depending on satellite cells, stem cells localized
under the basal lamina of the muscle fiber. Similar to myotubes (immature muscle fibers),
regenerating fibers express MHC-I on the sarcolemma and in the sarcoplasm.
Epidemiology
♀:♂= 2.5:1, for overlap 10:1, jDM 1:1 and IBM mostly in men. IIM has a 3-4:1 Black/White
ratio of incidence and a younger adult onset peak in Blacks. Incidence: 1-20/million per year,
prevalence 5-22/million. Peak age of onset is bimodal in distribution for DM: one peak at 5-
15yrs and the other at 45-65yrs. PM rarely occurs in patients <15yrs, with mean age of onset
50-60yrs. Geographical gradient north to south, most in equator (UV radiation?).
Causes
-Environmental: UV-radiation (Mi2), drugs (statins, GCs, immune-checkpoint inhibitors).
-Infectious: Coxsackie (jDM), flu, HIV, HSV and other viral
-Smoking
-Genetics: HLA-II (HLA DRB1*0301, DQA1*0501), PTPN22 (TCR signaling), IL-1, TNF.
-GVHD
Criteria
several limitations, including the inability to identify key clinical subsets such as IMNM and
CADM and the lack of inclusion of defined MSAs beyond anti-Jo-1 (back in 2017, other Abs
were not known).
,Clinical
Most common is insidious, progressive and painless symmetric proximal muscle weakness
(pain = IMNM or even PMR?) arising over the course of 3-6 months. jDM has a more acute
onset of disease, with fever, muscle pain and weakness developing in several weeks.
Fatigue is a prominent complaint in patients with IIM and fever is observed in jDM
and adults with ASyS. Weight loss may occur as in any systemic inflammatory disorder, but if
persistent and severe, associated malignancy should be considered.
Most patients fall into one of three categories: i) with only muscular symptoms, ii)
with only extramuscular symptoms (skin, ILD, arthritis), iii) with both (DM).
Overlaps
might affect more distal than proximal muscles + head drop
-with SSc: Raynaud, puffy fingers, sclerodactyly, distal esophageal dysmotility
-with SLE: photosensitivity, malar rash, alopecia, polyarthralgia, pleuritis, leukopenia
Skeletal muscle
The onset of muscle weakness is typically insidious, bilateral, symmetric and painless, with
involvement of proximal more than distal muscles, with weakness being disproportionally
greater than atrophy. An exception is IBM, in which asymmetric distal weakness and atrophy
are as prominent as the proximal muscle findings. Pelvic girdle is often affected initially
(while for PMR shoulders are a necessary criterion). Muscle pain may occur and is more
common in DM and IMNM, particularly with exercise. Ocular or facial muscle weakness is
very uncommon (consider other diagnosis), except for IBM. There can be ‘head drop’
because the neck flexor muscles are involved more than the extensors. Muscle atrophy and
joint contractures are late findings in chronic PM/DM, in contrast to IBM where muscle
atrophy is more common at initial evaluation.
Pharyngeal muscle weakness may contribute to dysphagia, hoarseness, nasal
regurgitation of liquids or aspiration pneumonia. Respiratory muscle weakness may
contribute to dyspnea, although ILD is a more common cause of pulmonary dysfunction.
Clues of non-immune-mediated myositides: involvement of facial muscles
(including oculomotor), asymmetry (exception IBM), winged scapula, slow progression,
fasciculations, exertional weakness, no response to GCs.
*One of the most common causes of myalgia is intermittent claudication.
Skin
Precedes, develops simultaneously with or follow the muscle symptoms. In DM skin
manifestations may precede in 30%.
•DM: Gottron’s papules (60-80%) and heliotrope rash (<50%) (can be pruritic) are
pathognomonic, Gottron’s sign (a macular erythema over other extensor areas such as the
elbows, knees and ankles), cutaneous photosensitivity, “V” sign, shawl sign, holster sign,
cuticular hypertrophy and hemorrhage with periungual erythema, calcinosis cutis,
telangiectasias, nailfold infarcts and capillary dilation. Later, the affected skin lesions may
become shiny, atrophic and hypopigmented with telangiectasias. DM often presents with
intensely pruritic areas of confluent, violaceous erythema on the scalp, face, upper trunk
and upper extremities and its presence differentiates DM from SLE, in which pruritus is
uncommon (heliotrope rash can be pruritic). Panniculitis presenting as erythematous,
tender, subcutaneous nodules on the lower or upper extremities is a rare manifestation.
•ASyS: “mechanic’s hands”
•MDA-5: skin and oral ulceration are characteristic.
•TIF-1γ: palmar hyperkeratotic papules, PsO-like lesions, "red-on-white" patches and
the ovoid palatal patch.
, •SAE: angel-wings
Calcinosis
More in jDM (especially black children), the younger the age the more serious and
associated with NXP2. In adults, chronic, active disease or with a delay in initial treatment.
Calcinosis may be intracutaneous, subcutaneous, fascial or intramuscular in location, with a
predilection for sites of repeated microtrauma.
Joints
Polyarthralgia and polyarthritis, if they occur, appear early in the course of disease. The
distribution is RA-like and generally mild. ASyS has higher incidence of arthritis and can be RF
(+). Joint findings are more common with overlap and ASyS, in which case they can be
chronic and deforming with instability of the interphalangeal thumb joint (“floppy thumb”
sign), erosions and periarticular calcifications.
Lung
ILD
The lung is the most common internal organ affected in PM/DM (20-80%), occurring also in
ASyS and overlap, while MDA-5 leads to RP-ILD. Dyspnea in patients with myositis has many
potential causes, including parenchymal and non-parenchymal problems such as respiratory
(diaphragmatic and intercostal) muscle weakness or cardiac dysfunction. However,
respiratory muscle weakness leading to respiratory failure or significant dyspnea is
uncommon (<5%). ILD is less common in patients with IIM associated with malignancy. Krebs
von den Lungen-6 (KL-6) [a glycoprotein localized on the membrane of type II alveolar
epithelial cells, mainly released by propagating or damaged type II alveolar epithelial cells,
and is specific for determining damage to these cells] is a useful biomarker reflecting disease
activity in various ILDs. For ASyS, ILD is more commonly seen in non-anti-Jo-1, whereas
myositis and arthritis were more in anti-Jo-1 patients.
The majority of patients with DM/PM who develop ILD have histopathologic and
radiographic patterns of NSIP or OP, who can also be present concomitantly. NSIP and OP
represent a more favorable histopathology, whereas UIP and DAD portend a more ominous
course. DM-ILD may be more commonly associated with DAD, thus indicating that
pulmonary histologic differences and CT findings may further distinguish PM from DM. In
addition, the concomitant finding of anti-Ro in patients with ASyS autoAbs may be
associated with more severe and progressive ILD.
Risk factors for ILD:
-clinical: ASyS, CADM
-lab: ASyS autoAbs, anti-MDA-5, Ro52
Screen for ILD: all IIM, except IBM. Follow-up with PFTs every 3−6months
during the first year and every 6−12 months thereafter, but CT every 3-6 months if RP-ILD,
otherwise annually.
PAH: as a result of hypoxemia-induced pulmonary vasoconstriction.
Diffuse alveolar hemorrhage with pulmonary capillaritis is uncommon but can be lethal.
Pneumomediastinum: associated with RP-ILD in the setting of CADM.
-CT: ground-glass (98–100%), reticular opacities (67–87%) and consolidations.
Honeycombing is rare.
-PFTs: restrictive and ↓ DLco.
Heart
, myocarditis, conduction abnormalities, arrhythmia. Symptomatic cardiac disease, such as
congestive heart failure, is less common, however, patients are also at increased risk for
myocardial infarction. SRP-IMNM is associated with cardiomyopathy.
Gastro
Dysphagia, regurgitation. Esophageal dysmotility is seen in both overlap disorders and pure
PM/DM. GI mucosal ulceration and hemorrhage as a result of vasculitis can occur in jDM.
NXP2 is associated with GI involvement (abdominal pain, melena and intestinal perforation).
Dysphagia may be caused by muscle weakness in the pharyngeal muscles or upper portion
of esophagus. Both upper and lower esophageal sphincters can be affected.
MCTD, SSc: only lower sphincter affected, while RA, IIM both.
-Dysphagia Dx: myasthenia Gravis, motor neuron disease, oculopharyngeal muscular
dystrophy, toxic myopathy, other IIMs, GVHD.
Vasculitic
Raynaud is most common in ASyS and SSc-overlap but is observed in all myositis subsets
except for malignancy associated myositis. The inflammatory vascular lesions of DM include
tender dermal and subcutaneous nodules, periungual infarcts and digital ulcerations.
Systemic vasculitis is common in jDM but uncommon in adults.
Renal
Renal disease is usually secondary to rhabdomyolysis. The presence of primary renal disease
should prompt a search for an associated CTD.
Subtypes
DM
nuclear origin: Mi2, TIF-1, NXP2, SAE
cytoplasmic origin: MDA-5
CADM
10-30%of DM cases. Patients are considered to have provisional CADM at 6 months and
confirmed CADM at 2 years. Perhaps >50% will develop muscle disease over time, but a
significant proportion will manifest skin-limited disease only (SAE). This form can be
associated with malignancy (TIF-1γ, NXP2), whereas other patients may develop
extramuscular manifestations such as RP-ILD (MDA-5) even in the absence of myositis. The
most associated MSA for CADM is MDA-5. A subset of patients, those with "hypomyopathic
dermatomyositis", will have minimal elevations of muscle enzymes or subtle abnormalities
on muscle studies in the absence of any objective or subjective weakness.
DM sine dermatitis
rarely patients can present with an IIM that on biopsy looks like DM (perivascular
inflammation with perifascicular atrophy) but have no skin manifestations of DM.
Association with NXP2, but can have other MSAs too.
ASyS
♀:♂=2/1, proximal muscle weakness is typically the first manifestation. ↑ CPK 5-10x. Most
patients have myositis (80%), ILD (66%) [NSIP ± OP > UIP, usually involving the lower lobes],
seronegative arthritis (60%), Raynaud (40%), rash (30%) and fever (25%). Mechanic’s hand
and hiker’s feet. Some may have DM-like rash with heliotrope or Gottron’s papules and no
mechanic’s hands. Rare association with cancer in older patients. Nailfold capillary
