Today we discussed a fascinating case of statin-related anti-HMGCR positive immune-mediated inflammatory myositis (also called necrotizing autoimmune myositis). The case highlighted the importance of a framework approach to diseases.
We first went over the framework for true muscle weakness, which can be anatomically divided as follows
Source: Frameworks for Internal Medicine (Dr. Andre Mansoor from OHSU). Available on Amazon (highly recommended!)
To help us localize the lesion to a myopathy, we used the following framework to determine that it was likely a myopathy.
The differential for myopathy is broad, and generally is the same for an elevated CK and non-traumatic, non-exertional rhabdomyolysis. The causes can be divided as follows. If you like mnemonics, think Drug-REGIIME for the various categories.
Once we narrowed the differential to an inflammatory myopathy, we utilized the following chart that guided us to the probable conclusion that it was an immune-mediated necrotizing myopathy (also known as necrotizing autoimmune myopathy). This was confirmed by a highly positive anti-HMGCR antibody
Adapted from a NEJM Article: https://www.nejm.org/doi/full/10.1056/NEJMra1402225
Clinical Pearls about INMN/NAM:
- Can occur in association with viral infections, malignancy, in patients with CTD such as scleroderma or in patients taking statins
- Can start acutely or sub-acutely with severe proximal muscle weakness and markedly elevated CK values of between 10-100k ULN (2K-20K)
- A rare diagnosis, but some experts believe that polymyositis is overdiagnosed and that INMN may actually be more common!
- Two antibodies are highly specific though not sensitive for the condition (anti-SRP and anti-HMGCR)
- The majority of anti-HMGCR positive cases are related to known exposure to a prescribed statin (~70%)
- Treatment is to discontinue the statin but most cases will require prompt immunosuppression
- Statin-induced muscular events are on a spectrum, and include the following:
- 1) Mildly elevated CK and myalgias
- 2) Rhabdomyolysis
- 3) Self-limited toxic myopathy
- 4) IMNM
- It is only IMNM that generally does not improve with merely cessation of the drug and it generally needs immunosuppression
- Biopsy is required to make the diagnosis but the presence of the antibody will often result much more quickly and in our case, the patient started on immunosuppresion prior to the biopsy results because the clinical profile fit perfectly with this diagnosis
Today’s case was a 60-year-old man with acute onset atypical chest pain, tachycardia, mild leukocytosis, and concave ST elevations without anatomical distribution, who was found to have acute pericarditis.
We learned about a patient who presented with a heat stroke during our recent heat wave. Remember the importance difference between fever and hyperthermia
Fever: elevation of hypothalamic set-point leading to increased core temperature
Hyperthermia: elevation of core temperature independent of changes in the body’s thermoregulatory center.
In clinical practice it is often difficult to discern the two – and therefore for challenging cases, it may be useful to think about the differentials for both. Remember, everyone NEEDs MISO 🙂
Thanks to Phuong today for presenting the case of a young woman who presented with volume overload, found to have constrictive pericarditis!
- Constrictive pericarditis and restrictive cardiomyopathy can have similar clinical presentations. Cardiac cath is generally needed to help distinguish between the two.
- The most common cause of constrictive pericarditis is idiopathic!
- Exam findings in constrictive pericarditis include volume overload, pulsus paradoxus, Kussmaul’s sign, pericardial knock, and occasionally (<20% of the time) pericardial friction rub.
- ECG and CXR can be normal in constrictive pericarditis.
- Treatment of early disease is supportive care. Treatment of late stage constrictive pericarditis is pericardiectomy.
Etiologies of constrictive pericarditis:
- Idiopathic (42-61%) ⇒ most common cause!
- Post-cardiac surgery (11-37%)
- Post-radiation therapy (2-31%) particularly after Hodgkin disease or breast cancer
- Connective tissue disorder (3-7%)
- Post-infectious – TB or purulent pericarditis (3-15%)
- Miscellaneous causes (malignancy, trauma, drug-induced, asbestosis, sarcoidosis, uremic pericarditis) (1-10%)
- Symptoms related to fluid overload
- Symptoms related to diminished cardiac output in response to exertion
- Elevated JVP
- Pulsus paradoxus – drop in SBP >10 mmHg due to drop in stroke volume and cardiac output with inspiration (20%)
- Kussmaul’s sign – lack of an inspiratory decline in JVP. (Also present in people with severe tricuspid valve disease or R heart failure.
- Pericardial knock – 47%
- Pericardial friction rub – 16%
- Stigmata of heart failure
- ECG: can be normal
- CXR: Majority of people do NOT have pericardial calcifications
- Interestingly, calcifications are more common in people with idiopathic disease, a longer duration of symptoms, and those with TB!
Management of Constrictive Pericarditis
- Early disease is usually managed with supportive care. Diuretics can help mitigate symptoms of volume overload but must be used cautiously due to preload dependent physiology.
- Late stage disease is treated with pericardiectomy. Complication rates tend to be high and operative mortality can reach 12%!
Constrictive Pericarditis vs Restrictive Cardiomyopathy:
We also talked about a helpful way of breaking up new onset ascites to help generate a DDx:
Today, we talked about the case of a middle aged woman with recent diagnosis of metastatic breast cancer on palliative Paclitaxel who was admitted with acute onset of bloody diarrhea found to have Shiga toxin and progression to HUS! She developed neurologic manifestations for which she underwent PLEX and is now recovering in rehab.
- TTP and HUS present very similarly and are difficult to distinguish clinically. HUS typically has worse renal failure than TTP and rarely has neurologic manifestations.
- Because they are tough to tease apart, start PLEX early if TTP is on your differential for HUS because TTP has a high mortality rate.
- Acute diarrhea requires work up in those with severe illness, inflammatory features, risk factors, persistent symptoms, or work in fields that are of public health related concern (food handlers, daycare workers, etc.)
- The most common cause of acute bloody diarrhea worldwide is shigella.
- Bloody diarrhea with a normal fecal leukocyte/lactoferrin count is highly suggestive of E. histolytica.
- Majority of shiga toxin produced in adults is by E coli.
- Avoid antibiotics if possible in a patient with bloody diarrhea due to shiga toxin as it can precipitate HUS.
Indications for work up of acute diarrhea:
- Age >65
- Significant volume depletion
- Blood in stool
- Severe abdominal pain
- Recent antibiotics
- Known or suspected IBD
- Food handler, daycare worker, healthcare worker
- Recent travel
DDx for acute bloody diarrhea:
- Ischemic colitis
- Invasive infections
- Shigella (most common)
- EHEC and EIEC (most commonly associated with shiga toxin)
- Nontyphoidal salmonella
- Entamoeba histolytica
- Schistosoma (more common in resource limited settings)
Work up for acute bloody diarrhea:
- Enteric pathogen panel (NAAT):
- Campylobacter, salmonella, shigella species, vibrio, yersinia, shiga toxins, norovirus, and rotavirus
- Stool culture
- Grows campylobacter, Shigella, Salmonella, and E coli strains. If suspecting other organism, must specifically request that culture from lab
- Stool leukocytes or lactoferrin
- More helpful if negative to rule in amebiasis.
Shiga toxin mediated hemolytic uremic syndrome
- Characterized by the triad of MAHA, thrombocytopenia, and acute renal failure. Rare neurologic manifestations can occur as in our patient.
- Other clinical symptoms ⇒ bloody stools, absence of fever, WBC>10k, and abdominal pain.
- 23-47% require hospitalization
- 6-9% of people infected with EHEC (O157:H7 and O104:H4) can go on to developing HUS and it is much more common in children.
- Ingestion of undercooked beef and E coli
- Shiga toxin produced by E coli binds to vascular endothelial cell surface, thereby inhibiting protein synthesis, generating lots of cytokines and chemokines, and causing end organ damage and thrombosis.
- Clinical course
- HUS develops 5-10 days after onset of diarrhea
- Up to 50% of patients require dialysis and 39% have long term renal injury.
- Mortality is 3-5%
- Supportive care is the mainstay
- Some data from an outbreak in Germany suggests there may be benefit to plasma exchange (PLEX) via removal of shiga toxin and prothrombotic factors from the body
- Eculizumab ⇒ beneficial in patients with complement-mediated HUS (not shiga-toxin mediated)
- Main distinguishing features from HUS
- Renal failure can often be mild
- Neurologic impairment is more common
- Mortality rates are much higher
- Confirmatory test is ADAMTS13
- Mainstay of treatment is PLEX!
Moral of this story: start PLEX while you’re waiting to decide if it’s HUS or TTP!
Thanks to Paige for presenting the case of a middle aged homeless man who presented with heart failure exacerbation, found to have digital ischemia and subsequently diagnosed with scleroderma and likely contribution from cocaine-induced Raynaud’s!
- Break digital ischemia down to its culprit vessels to help you formulate a DDx: large, medium, and small (see below)
- Raynaud’s phenomenon can be primary (idiopathic) or secondary to autoimmune conditions, hematologic disorders, drugs/toxins, environmental factors, or hypothyroidism.
- Treatment of Raynaud’s involves avoiding known triggers, calcium channel blockers, and phosphodieterase inhibitors.
- Three antibodies are associated with scleroderma: anti-centromere (limited cutaneous systemic sclerosis), anti-Scl70 (diffuse cutaneous systemic sclerosis), and anti-RNA polymerase III (diffuse cutaneous systemic sclerosis). Patients with the latter antibody are more likely to develop scleroderma renal crisis.
- Avoid steroids in patients with scleroderma because they can precipitate renal crisis!
- Arterial dissection
- Thoracic outlet
- Thromboangiitis obliterans (Buerger’s disease)
- Hypercoagulability (APLS, DIC)
- Other connective tissue diseases
- Exaggerated vascular response (vasospasm) to cold temperature or emotional stress, manifested by discomfort and sharply demarcated color changes of the skin of the digits.
- Primary Raynaud’s: Those without a definable cause, idiopathic
- Onset is 15-30 years
- More common in women
- Occurs in multiple family members
- Higher prevalence in people with fibromyalgia and migraines though unclear linkage.
- Secondary Raynaud’s: There is a cause
- Autoimmune rheumatic diseases
- Systemic sclerosis, SLE, MCTD, sjogren’s, DM/PM
- Drugs/toxins: cocaine, amphetamines, chemo (cisplatin, bleomycin)
- Hematologic abnormalities: cryoglobulinemia, cold agglutinin disease, paraproteinemia, POEMS, cryofibrinogenemia
- Occupational/environmental: vascular trauma, use of vibrating tools, frostbite, CTS
- Linear scleroderma
- Systemic cutaneous
- Face, hands, feet
- 10-15% of patients may develop pHTN, ILD, or CREST
- >70% survival at 10 years
- Anti-centromere antibody
- Early and significant renal, ILD, GI, and myocardial disease
- Survival 50-60% at 10 years
- Anti-RNA polymerase III
Screen for malignancy in patients with new diagnosis of scleroderma!
- ILD (75%)
- Pulmonary HTN (10-40%)
- Lung cancer
- GI (90%):
- Esophageal dysmotility (GERD-like symptoms)
- Scleroderma renal crisis (15%)
- Inflammatory arthritis (rare)
- Digital ischemia,
- Pulmonary HTN,
- Scleroderma renal crisis
- Avoid steroids (it can precipitate scleroderma renal crisis)
- Biologics: modest benefit to slow progression/severity of complications if started early in disease course
- Otherwise, treatment is organ based
BONUS Thromboangiitis obliterans (Buerger’s disease)
- Nonatherosclerotic, segmental, inflammatory disease that affects the small to medium-sized arteries and veins of the extremities
- Usually young smokers
- Associated primarily with tobacco products but cannabis arteritis has also been reported and is clinically indistinguishable.
- Can present with superficial thrombophlebitis, Raynaud’s, digital ischemia, other organ ischemia (cerebral, coronary, internal thoracic, renal, and mesenteric arteries), or joint complaints.
- Work up
- Labs to rule out other similar disorders:
- Acute phase reactants
- Immunologic panel – ANA, RF, complements, anticentromere antibody, anti-scl70
- Complete hypergoabulability screen
- Tox panel for cocaine, amphetamines, and cannabis
- ABI: a normal ABI does not rule out this disease because vessel occlusion could be limited to distal vasculature. Could perform digit plethysmography or toe pressures to confirm. Abnormal test is not specific to TAO.
- Vascular imaging:
- MRA or CTA may not provide sufficient spatial resolution for the distal digits so it’s best to image the entire aorta and upper and lower extremities for evidence of disease that has not yet clinically manifested itself.
- Angiographic findings would be similar to patients with cocaine, amphetamine, or cannabis ingestion related digital ischemia.
- PAD: usually only in lower extremities as opposed to both upper and lower.
- Thromboembolic disease
- Repetitive trauma
- Smoking cessation
- Intermittent pneumatic compression for lower extremities.
- IV prostaglandins (iloprost) à best studied but not very practical because it’s a 6 hour daily infusion
- Phosphodiesterase inhibitors (cilostazol, sildenafil, tadalafil)
- CCB (nifedipine)
- Largest series of 224 patients who stopped smoking had a vascular event-free survival of 41% at 5 years and 23% at 10 years.
- Amputation free survival was 85, 74, and 66% at 5, 10, and 15 years