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
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
3) Self-limited toxic myopathy
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
Thanks to John for presenting the case of a middle aged man from Vietnam with history of smoking who presented to the hospital with painless jaundice with imaging concerning for malignancy, found to have IgG4 related autoimmune pancreatitis!
For imaging of the biliary tree:
Ultrasound is best for stones
CT is better for parenchymal disease
ERCP/MRCP is best for intraductal masses or stones
IgG4 related disease is more common in men >50 years of age. It can affect many organs, similar to sarcoid.
It is an inflammatory and fibrotic systemic conditions where organs form tumefactive lesions rich in IgG4 plasma cells.
Diagnosis requires biopsy. Serum IgG levels may be normal even in active disease. However, a significantly elevated level is highly sensitive/specific (>95%) for IgG4 related disease.
Thanks to Grace for presenting the case of a middle aged man who presented with chronic weight loss, acute SOB, and splenomegaly on exam, found to have a WBC of 188 on work up and chest imaging concerning for leukostasis.
Most common cause of splenomegaly is portal HTN. But the ddx is broad (see schema below).
Most common cause of a WBC 25k-75k is infection (C diff)
WBC >100k is leukemia until proven otherwise.
Leukostasis is symptomatic hyperleukocytosis, most commonly associated with AML.
Management involves lowering the WBC by leukapharesis, hydrea, and TKIs (if CML) and preventing TLS.
Defined as symptomatic hyperleukocytosis and is a hematologic emergency!
Mortality rate can be as high as 40% within the first week of presentation.
Clinical manifestations of ischemia primarily in CNS, MI, lungs, and kidneys. Can also see limb ischemia and priapism.
Malignancies at highest risk of leukostasis in order of prevalence:
AML (WBC >50k)
ALL (WBC >100k, though tends to present with TLS and DIC much more commonly than leukostasis)
CML (WBC >100k), generally if in myeloid blast crisis
CLL (WBC >400k)
FLUIDS, lots and lots of fluids
Cytoreduction: lowers the WBC
Leukapharesis: not readily available as it requires a dialysis line and trained nursing staff
Hydroxyurea: to lower the WBC
Tyrosine kinase inhibitors (especially for CML related leukostasis)
Induction chemo (for non-CML related leukostasis)
Prevent tumor lysis syndrome:
Uric acid lowering therapy
In hemodynamically stable patients AVOID TRANSFUSION – it’s like adding fuel to the fire and can worsen ischemia. Platelet transfusion is less dangerous than RBCs and you may have to do it before trialysis line placement.
↑K, ↑Phos, ↑uric acid, ↑creatinine, ↓calcium
Occurs in bulky or chemosensitive tumors with high proliferative rate (Burkitt’s lymphoma, acute leukemias, small cell lung cancer)
Allopurinol takes 1-2 days to show effect and does not reduce preexisting elevated uric acid levels so use rasburicase if uric acid already high or preemptively if TLS risk is high or if there is kidney injury.
HD if concern for renal damage
Causes of pseudohyperkalemia
Technique of blood drawing (tourniquets and fist pumping)
Thanks to Erica for presenting the case of a middle aged man who presented with acute back pain and B symptoms after trauma to his back, found to have stage 3B multiple myeloma.
Remember that majority of cases of acute low back pain (<6 weeks) is due to musculoskeletal etiologies that spontaneously improve on their own. Imaging and further diagnostic work up is not indicated unless there are red flags (see below).
A straight leg test is more useful when negative as it has a high negative predictive value for ruling out radiculopathy. False positive rates are quite high.
Unexplained anemia and worsening renal function in the outpatient setting should trigger a work up for multiple myeloma.
The most common presenting symptoms for MM are anemia (73%), bone pain (58%), and renal insufficiency (48%).
In diagnosing MM, sensitivity increases with each added test: SPEP (82%) → IFE (93%) → FLC/UPEP (97%). The other 3% that would not be diagnosed with these tests have a non-secretory MM (monoclonal increase in plasma cells in bone marrow that do not produce immunoglobulins or light chains).
Red flags for acute low back pain:
Focal neurologic complaints/deficits
History of cancer
Age >50 years
Fever not explained by another cause
History of recent bacteremia or IVDU
Pain that is worse at night
No relief with bed rest or pain lasting >1 month
Multiple Myeloma: refer to this prior blog post. Other info below:
SPEP: picks up M protein or elevated immunoglobulins (heavy + light chain) in the serum. You can diagnose over 80% of patients with MM using an SPEP.
IFE: identifies the specific type of immunoglobulin that is elevated with its light chain.
Free light chains (FLC): measures the amount of free light chains not bound to a heavy chain floating around in the blood. Normally people have about a 2:1 ratio of kappa to lambda chains. In light chain only multiple myeloma, there is a disproportionate increase in one type over the other and the ratio will be off. If there is an increase in both light chains but the ratio is normal, think kidney disease!
Keep in mind that the reason to check FLC when you suspect MM is to diagnose those people who are only producing light chains and not whole immunoglobulins that would have been picked up by SPEP/IFE.
UPEP: measures light chains dumped in the urine (Bence Jones protein)
Thanks to Jess for presenting the fascinating case of a middle-aged woman with family history of autoimmune disease who presented with acute onset of fatigue and abdominal pain, found to have vitiligo on exam. Work up revealed hyponatremia due to a secondary adrenal insufficiency, pancytopenia, and panhypopituitarism possibly due to a yet to be diagnosed autoimmune disorder!
Remember that hyponatremia is a problem of water regulation that can be compounded by low solute intake.
Primary adrenal insufficiency is disorder at the level of the adrenal glands and manifests with low sodium and high serum potassium levels.
Secondary adrenal insufficiency is disorder at the level of the pituitary and manifests with low/normal sodium and normal potassium levels (because low cortisol leads to high ADH levels and hyponatremia).
Make sure to do work up to rule out panhypopituitarism. Keep in mind that the most sensitive test for HPA access integrity is LH/FSH.
Tertiary adrenal insufficiency is disorder at the level of the hypothalamus and presents similarly to secondary AI.
Test for adrenal insufficiency with a cort-stim test and/or AM cortisol and ACTH levels.
Remember these three steps to working up hyponatremia:
Is there a sodium problem? check serum osm
Are the kidneys responding appropriately? check urine osm
Is ADH revved up for a hemodynamic reason? check urine Na
Failure of adrenal glands
Causes: Addison’s (most common in the US), infiltrative processes (TB, sarcoid), hemorrhage, toxins
Labs would show ↓Na and ↑potassium (b/c aldosterone is gone)
Failure of pituitary (low ACTH)
Causes: pituitary lesions, surgeries, TBI, drugs
Clinically may present with loss of other anterior pituitary hormones
Labs would show ↓Na (because low cortisol leads to high ADH levels) but normal potassium levels (b/c aldosterone is active)
Failure of hypothalamus (low CRH)
Causes: more commonly iatrogenic (cessation of high dose glucocorticoid therapy without taper) or post surgical interventions.
Inflammation of the pituitary
Four categories based on histologic findings:
Most common form
Seen in late pregnancy and post-partum period
Also associated with CTLA4 inhibitors like ipilimumab
Idiopathic or secondary to GPA, sarcoid, TB
Xanthomatous (most rare)
Headache out of proportion to exam findings
Preferential decrease in ACTH and TSH ⇒ adrenal insufficiency and hypothyroidism
Pituitary size eventually normalizes but pituitary loss of function is often permanent.
Thanks to Audris for presenting the case of a middle-aged man with vasculopathy on ACEi who presented with angioedema requiring intubation! We discussed the diagnostic work up and management of angioedema as well as hyperkalemia!
First order of business when suspecting angioedema is the ABCs!
Treat angioedema in the acute setting with H1 blockers and steroids, even if you are suspicious of a non-histaminergic pathway.
Always assess for concurrent anaphylaxis (hypotension or bronchospasm in addition to hives or angioedema). If anaphylaxis is present, then treatment involves IM 0.3-0.5 mg of 1:1000 dilution epinephrine (1mg/mL), repeat every 20 minutes until symptoms resolve (max 3 doses)
If you have access to a functioning kidney, favor loop diuretics over cation exchange binders (i.e. kayexalate) to lower serum potassium!
Patiramer is much better tolerated than kayexalate and has a more favorable side effect profile.
Calcium gluconate has a role in the treatment of hyperkalemia when EKG changes are present. Give a dose and repeat the EKG. If no improvement, repeat to a maximum of 3 doses until EKG has normalized.
3 pathophysiologic subtypes:
Mast cell/histamine mediated
Allergic reactions: food/insect stings, latex, drugs. Can also be idiopathic. IgE type 1 hypersensitivity
Direct mast cell release: drugs (opiates, contrast). IgE is not involved.
ASA/NSAIDs: via IgE or direct mast cell release
Chronic urticaria w/w/o angioedema
S/sx affecting organ systems other than the skin? Suspicious for anaphylaxis ⇒ give epi
Treatment: H1 blockers, glucocorticoids.
Inhibition of enzymes involved in the degradation of bradykinin, or deficiency/dysfunction of complement C1 inh
More prolonged time course, develops over 24-46 hours and resolves within 2-4 days
Relationship between trigger and onset of symptom is not as apparent
Not associated with other s/sx. More common to have abdominal pain due to bowel wall involvement.
Other drugs: sirolimus, everolimus, amiodarone, metoprolol, risperidone, paroxetine, and etanercept, inhaled cocaine.
Hypereosinophilic syndrome and Gleich syndrome
Agents that reduce serum potassium via transient intracellular shift:
Insulin: give with D50 if normoglycemic to avoid hypoglycemia and be sure to check FSG hourly for 4 hours after to ensure no hypoglycemia develops
Albuterol (10-20 mg) nebs: this is significantly higher than the dose we give in COPD (2.5 mg) and is equal to ~8 treatments! So make sure to continue the nebs when the patient arrives on the floor from the ER if they are still hyperkalemic.
NaHCO3: best for management of chronic hyperkalemia in the outpatient setting. In the acute management of hyperkalemia, alkalinization of serum with a large bicarb load can lead to a reduction in serum calcium levels. Lower serum calcium can lead to more cardiac membrane instability and fatal arrhythmias!
Agents that eliminate potassium from the body:
Loop diuretics: first choice if a functioning kidney is available!
Cation exchange binders: preferred when kidneys are not available
Patiramer (available at VMC), much more tolerable than kayexalate and highly effective at lowering serum potassium. Like kayexalate, it works over hours to days.
Sodium zirconium: similar to patiramer but not currently available
Kayexalate: not pleasant to take orally. Also carries with it the slight risk of colonic ischemia especially in post renal transplant patients and those with baseline colonic dysfunction (due to infection or inflammation).
Indication for using calcium gluconate: when EKG changes are noted. Repeat doses (maximum 3) until EKG changes have resolved.
Today, we discussed the case of a Vietnamese man who presented with chronic cough, 40 pound weight loss, and joint pain, found to have cavitary lesions in his lungs with work up revealing pulmonary TB as well as tophaceous gout on urate-lowering therapy with allopurinol leading to SJS/TEN.
Cavitary lung lesions have a broad differential (see below) aside from TB.
Risk factors for developing SJS/TEN include HIV (100x higher risk), genetics (especially Asians and South Asians), autoimmune diseases, malignancy, and high dose/rapid infusion of offending meds. Consider genetic testing prior to starting meds associated with this allergy (allopurinol, sulfa drugs, PCNs, AEDs, etc.) in at risk populations.
Nikolsky sign can be positive in SJS/TEN, staph scalded skin syndrome, and pemphigus vulgaris
Time of onset is 1-3 after starting the offending drug
SCORTEN score is useful for determining prognosis
Early use of cyclosporine in patients with SJS/TEN has shown significant reduction in mortality.
SJS/TEN (Steven Johnson vs toxic epidermal necrolysis)
< 10% = SJS, > 30% = TEN, in between = Overlap
Abx (PCN, quinolones)
Infx: Mycoplasma, graft-vs-host
HIV (100x higher risk)
There are a lot of them (check on uptodate for specific drugs) but a couple examples are:
Patients with this positive gene has higher risk for severe cutaneous hypersensitivity reaction to allopurinol including SJS and TEN. High risk Asian populations carrying this gene are Korean, Thai and Han Chinese.
HLA-B*15:02 is recommended before starting carbamazepine in Asians and South Asians
Cytochrome CYP2C19 polymorphism
High doses and rapid infusion of medications
1-3 weeks after offending drug
Influenza-like symptoms (malaise, myalgias, arthralgias) x 1-3 days
Conjunctival itching or burning
Acute onset macules over face, trunk, may form flaccid bullae
Positive when shear stress on the skin i.e. rubbing results in exfoliation. Indicates a pathology at the dermal/epidermal junction.
Staphylococcal scalded skin syndrome
Asboe-Hansen sign (AKA bullae spread sign)
Mucous membrane involvement.
Eyes, mouth lesions
Mortality with SJS is 10%, TEN 30%
Supportive care for skin
Prevention of vulvovaginal sequelae
Evaluate for loss of surface epithelium
Saline rinses to remove debris
If extensive sloughing, then amniotic membrane transplantation (prokera ring)
Steroids: may lead to higher rates of complications
IVIG: conflicting data
Cyclosporine: one large case series from Spain and two systematic reviews have shown that cyclosporine given at 3 to 5 mg/kg may slow the progression. Inhibits T cell activation and thus prevents the production and release by cytotoxic T cell and natural killer cells of cytokines that could propagate SJS/TEN.
A study on 71 patients of whom 49 were treated with cyclosporine and 22 with other therapies found mortality rates were 10% and 32% respectively. Expected mortality based on SCORTEN for the cyclosporine group was 24% and 29% in the other group.
A 2018 meta-analysis on 255 patients with TEN found that treatment with cyclosporine was associated with a 70% reduction in mortality risk
Bonus info on gout:
Colchicine (avoid in severe renal or hepatic impairment or with meds that inhibit CYP450 system)
Indications for urate-lowering therapy for chronic treatment
Frequent or disabling gout flares
Clinical or radiographic signs of joint damage
Tophaceous deposits in soft tissues or subchondral bone
Gout with renal insufficiency (CrCl<60)
Recurrent uric acid nephrolithiasis
Urinary acid excretion >1100 mg/day)
Goal uric acid is <6mg/dL
Agents for chronic management
Xanthine oxidase inhibitors
Allopurinol, lower dose for CKD3 or higher renal disease
Febuxostat, very expensive, cardiovascular and hepatic side effects
Uricosuric drugs: ineffective if CrCl<50. Can worsen kidney injury. Avoid use if GFR <30
Pegloticase, fast improvement of symptoms, contraindicated in G6PD deficiency