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
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
Thanks to Eric for presenting the case of a young woman who presented with acute onset of night sweats, chest pain, and fatigue on subacute symptoms of cough and unintended weight loss, with CT chest showing mediastinal fatty infiltration which turned out to be thickening of the aortic arch and descending arteries consistent with Takayasu arteritis!
- The two main large vessel vasculitides are Giant Cell arteritis (GCA) and Takayasu arteritis.
- Takayasu primarily affects young women with the greatest prevalence of disease noted in Asia. GCA primarily affects older patients (>50 years).
- There is no diagnostic test to help with diagnosing Takayasu arteritis and for obvious reasons, biopsy is usually not possible. Some diagnostic criteria have been established to help (see below) and imaging tends to be the most helpful.
Thanks to Dr. Szumowski for sending us the case of a middle aged man who presented with acute L knee swelling and pain one week after a viral URI syndrome, initially concerning for septic joint. His clinical course was complicated by recurrent high daily fevers, a diffuse maculopapular rash, and knee arthrocenteses and joint washes that were clean leading to a diagnosis of Still’s disease!
- Still’s disease is a diagnosis of exclusion! Yamaguchi criteria can help with ruling in the diagnosis.
- Still’s remains a multi-systemic disorder of unknown etiology because it’s difficult to diagnose and rare (0.16 cases per 100,000).
- RF and ANA are generally negative but can be positive in <10% of patients with Still’s in low titers.
- ~66% of patients present with sore throat secondary to cricothyroid perichondritis or aseptic nonexudative pharyngitis.
- The disease is often recurrent. Predictors of poor outcome include erosive polyarthritis on presentation and shoulder/hip involvement.
- Described in 1897 by George Still, it is a systemic inflammatory disorder of unknown etiology
- Some clarifications on nomenclature:
- Systemic juvenile idiopathic arthritis (sJIA): first presentation <17 years old, previously referred to as Still’s disease
- Adult onset Still’s disease (AOSD): first presentation > 17 years old
- Epidemiology of AOSD:
- 0.16 cases per 100,000
- No sex predominance (F=M)
- Bimodal age distribution with peak between 15-25 and another 36-46 years of age. New diagnosis in patients >60 have been reported.
- Poorly understood but likely a combination of genetic predisposition, environmental triggers (viruses such as echo, coxsackievirus B4, mycoplasma, yernisnia, lyme, etc), activated innate immunity leading aberrant production of pro-inflammatory cytokines
- High ESR and CRP
- Very high ferritin levels
- Ultimately a clinical diagnosis so it’s important to exclude potential mimickers
- Yamaguchi criteria are the most sensitivity (93.5%)
- Fautrel’s Criteria are the most specific (98.5%)
- Largely empirical since clinical trial data is lacking
- High dose steroids are first line when systemic symptoms predominate
- MTX is second line
- NSAIDs are not good
- Biologic agents for refractory cases (IL1 antagonist anakinra or canakinumab), IL6 antagonist tocilizumab, or TNF inhibitors.
- Poor prognostic indicators:
- Hip and shoulder involvement
- Erosive polyarthritis at initial diagnosis
Thanks to Jen for presenting the case of a middle-aged lady with h/o HTN on hydralazine and PE noted to have progressively worsening glomerulonephritis and a discoid skin rash, with anti-MPO and anti-histone antibody positive serologies concerning for drug-induced ANCA associated vasculitis!
- Many cases of drug-induced lupus are actually drug-induced ANCA vasculitis!
- Medications associated with drug induced ANCA-vasculitis include hydralazine (most common and most severe presentation), followed by methimazole/PTU, and minocycline.
- Drug-induced vasculitis tends to present with anti-histone antibody positivity (sensitive but less specific). Drug-induced ANCA vasculitis can be anti-MPO positive especially in the case of hydralazine.
- Treatment involves witholding the offending agent. In the case of hydralazine induced ANCA-vasculitis, steroids and additional immunosuppressive therapy (cytoxan or rituxan) are also indicated to reduce progression to ESRD.
- >500 eos ⇒ eosinophilia
- > 1500 eos ⇒ severe eosinophilia
- > 5000 eos ⇒ severe eosinophilia at risk of end organ damage
- Etiology (NAACP-P)
- Monoclonal leukemias (eosinophil proliferation)
- Polyclonal: T cell lymphomas, Hodgkin lymphoma, some solid organ tumors (cervical, ovarian, gastric, colon, urotherlial, and squamous cell carcinomas)
- Adrenal insufficiency (super rare)
- Parasites: remember that only multicellular parasites can cause eosiniphilia
- Other bugs: ABPA, cocci, HIV
- Primary eosinophilic syndromes
- M:F is 1:1 but hydralazine induced lupus is more common in women
- Mechanism is poorly understood and genetic predisposition may play a role. More likely to happen in patients who are slow acetylators
- Anti-histone antibodies: 95% sensitive
- Other antibodies are uncommon
- Drugs: long list!
- Procainamide, hydralazine, chlorpromazine, quinidine, minocycline, PTU, statins, anti-TNF agents, IFN, methyldopa
- Weaker associations: AEDs, antimicrobials, beta blockers, lithium, HCTZ, amiodarone, cipro etc.
- Stop offending agent
- Joint symptoms: NSAIDs
- Skin symptoms: topical steroids
- Hydral-induced vasculitis: need cytotoxic or other immunosuppressive therapy. Treatment similar to ANCA positive vasculitis
- Resolution of symptoms weeks to months
Drug induced ANCA positive vasculitis:
- Patients typically present with constitutional symptoms, arthralgias/arthritis, and cutaneous vasculitis
- Strongest association with hyperthyroidism meds, hydralazine, and minocycline (hydral is the most common)
- Rare, but should be aware of this association because it impacts management and because it is often not diagnosed until too late in the disease course. In fact, many cases of drug induced lupus are actually drug induced ANCA-associated vasculitis
- In a small case series of hydral-induced ANCA-associated vasculitis of 10 patients, 90% had renal involvement of whom 7 recovered at 6 month follow up (though one required HD).
- Hydralazine-induced ANCA vasculitis is generally p-ANCA pattern with anti-MPO positivity (might also have anti-lactoferrin or anti-elastase)
- Treatment involves immunosuppression with steroids and cytoxan or rituxan.
- Non-hydralazine drug-induced ANCA vasculitis is typically treated with stopping the offending agent and has a better prognosis than its hydralazine-induced counterpart. In fact, ANCA positivity without clinical vasculitis is common especially in cases involving PTU.
We recently had a case of a middle age man with SLE on chronic prednisone, ESRD on PD, presenting with acute on chronic shoulder pain x 10 days. Presentation was initially concerning for septic arthritis, and joint washout revealed gross purulence from the shoulder joint. Cultures were sent but no additional fluid studies were obtained.
A subsequent TTE, and later a TEE, confirmed a mitral valve vegetation concerning for concurrent infective endocarditis. However, multiple sets of blood cultures, fungal cultures, synovial fluid culture from the initial I&D/wash out, and even 16S PCR of the synovial fluid were all negative. This is a rare case of culture negative endocarditis which is later thought to be more likely Libman Sacs!
- Risk factors: Advanced age, pre-existing joint dz, recent surgery or injection, SSTI, IVD, indwelling catheter, immunosuppression.
- Most cases arise from hematogenous seeding, hence bacteremia is common.
- Direct inoculation: usually due to trauma, surgery/injections, or wounds.
- Usually mono-microbial, and Staph aureus is the most common cause of septic arthritis in adults.
- GNR can be seen in older adults or in immunocompromised patients
- Monoarthritis is most common
- Edematous, painful, warmth, limited ROM
- Older patients may not be febrile
- 20% of cases can present as oligoarticular or polyarticular infection. Polyarticular septic arthritis is more likely to occur in pts with RA
- Most common affected joint is the knee
- Could be a manifestation of infective endocarditis, esp amongst IVDU
- Synovial fluid analysis and culture, should be obtained prior to abx
- Positive gram stain or culture is gold standard and diagnostic
- PCR only required in rare cases since most non-gonococcal cultures obtained prior to antibiotics return positive. Negative cultures can result due to recent abx or atypical organism.
- In pts with purulent synovial fluid (WBC 50k-150k) but culture negative, a presumptive dx can be made.
- Likelihood of septic arthritis inc with inc leukocyte count
- Blood cultures should be obtained
- Should also evaluate for endocarditis given most common organism is staph aureus
- Always get a radiograph to evaluate for concurrent bone/joint involvement
- CT/MRI can be useful if looking for an effusion
- Gonococcal arthritis
- Lyme disease
- TB arthritis
- Viral (usually polyarticular), i.e. Zika, Dengue, chikungunya, parvo, rubella, adenovirus
- Crystal dz
- Reactive arthritis
- Joint drainage, severe infectious may require repeated aspiration or even wash out.
- Most cases are staph, MRSA cases on the rise
- Suspect pseudomonas if pt is immunocompromised or has h/o IVDU
- Intra-articular abx: typically not used
- Staph aureus with bacteremia: At least 4 weeks
- Staph aureus without bacteremia: at least 14 days IV, followed by 1-2 weeks PO
- Bone involvement: 4-6 weeks
- Any organisms, any bone involvement: 4-6 weeks
- Other organisms: Typically at least 4 weeks
Culture Negative Endocarditis
- Definition: Endocarditis without an identified organism in at least 3 independent blood cultures with negative growth after 5 days
- 2-7% of IE cases
- 3 most common causes:
- Previous abx
- Inadequate samples
- Atypical organisms (fastidious bacteria i.e. zoonotic microbes, fungal)
- Farm animal exposure: Brucella, Coxiella (Q-fever)
- Homeless: Bartonella Quintana
- Cat: Bartonella hensale
- Ingestion of unpasteurized milk: Brucella, Coxiella
- Immunocompromised: Fungi, Coxiella
- HACEK: Most common agents of culture negative endocarditis
- Haemophilis aphrophulus
- Cardiobacterum hominis
- Eikenella corrdens
- PCR, histology, special cultures are helpful.
- 16S Ribosomal DNA: Bacteria
- 18S Ribosomal DNA: Fungi
- Non-infectious DDx
- APLS, associated with Q fever
- Acute rheumatic fever
- Atrial myxoma
- Libman Sachs endocarditis (non-bacterial thrombotic endocarditis or NBTE)
- Seen in:
- Advanced cancer
- Hypercoagulable state
- Mural thrombus
NBTE (Non-bacterial thrombotic endocarditis)
- Rare affected all age group with no sex preference, most commonly 40s – 80s
- Most commonly associated with pts with concurrent SLE or advanced malignancy (lung cancer, pancreatic cancer, gastric cancer)
- Other associated conditions: APLS, rheumatic heart disease, RA.
- A form of non-infectious endocarditis characterized by deposition of thrombi on halve valves, most commonly mitral or aortic
- Usually asx but high risk of thromboembolic events
- May present with acute stroke or coronary ischemia
- Exclusion: Demonstration of vegetations on echo in absence of systemic infection in patients with risk factors.
- Systemic anticoagulation
- Clinical experience and retrospective studies had shown this is beneficial due to high rate of emboli in pts with NBTE
- Treat underlying condition
- Surgical excision for NBTE vegetation, can be considered in only selective cases and generally avoided.
Today we went over a case from the HumanDx Project (Credit goes to Dr. Maki Cronin, SSM Health St. Louis University Hospital). A young woman presents with 5 months of cough, dyspnea, and unintentional weight loss over the past 5 months in setting of working at an in-door oyster mushroom farm for the past 8 months. She was tachycardic and febrile on presentation, with crackles and clubbing on exam. CT revealed e/o fibrosis and GGO, and BAL revealed significant lymphocytosis. This presentation is consistent with a diagnosis of hypersensitivity pneumonitis, and more specifically, mushroom worker’s lung!
Hypersensitivity Pneumonitis (HP)
This condition has many faces/names:
- Bird fancier’s lung (feathers, bird droppings)
- Cheese-washer’s lung (Cheese Fancier per Sarasa)
- Coffee worker’s lung
- Compost lung (aspergillus)
- Farmer’s lung (moldy hay)
- Hot tub lung (hot tubs)
- Mushroom worker’s lungs (mushroom)
- Sauna worker’s lungs (contaminated sauna water)
- Wine-grower’s lung (moldy grapes)
- 300 known antigens so far, most common (accounting for 75%) are:
- Water contamination
- Hypersensitivity to an environmental antigen leading to a type IV hypersensitivity reaction (they love asking these questions on tests for some reason) in genetically susceptible patients
- Type 1: IgE mediated, immediate onset (min to hours)
- Ex: Food allergies, PCN allergy, insect sting
- Type 2: Cytotoxic hypersensitivity, Ab-mediated cell destruction
- Drug induced cytopenias, Graves thyroiditis
- Type 3: Immune complex formation
- Ex: serum sickness, Arthus reactions, vasculitis, drug fever
- Type 4: Cell-mediated delayed hypersensitivity
- Activation of T-cells
- Hours or days after antigen exposure
- Ex: Tuberculin sensitivity, contact dermatitis, HP
- Interstitial inflammation and infiltration with lymphocytes, later on granulomas and fibrosis develop over time
- Occurs in sensitized pts with high level antigen exposure
- Fever, chills, cough, chest tightness, dyspnea, nausea 4-8 hours after exposure
- Exam: Tachypnea, inspiratory crackles, no wheezing
- Occurs in pts with long-term low-level exposure
- Months to years onset of exertional dyspnea, cough, fatigue, weight loss
- Clubbing, fevers are uncommon but can happen
- Over time: Pulmonary fibrosis, resp failure
- Falls between acute and chronic forms
- A combination of clinical suspicions with exposure history, with assistance of imaging
- CXR: Neither sensitive nor specific, may show reticular or nodular opacities
- HRCT: typically shows profuse centrilobular nodules, predominantly GGO, more chronic exposure will lead to fibrosis, traction bronchiectasis
- Mosaic pattern with areas of GGO is classic
- More chronic picture leads to fibrosis, which can lead to traction bronchiectasis
- Bronchiectasis is a chronic condition where the walls of the bronchi are thickened from inflammation and infection.
- PFT: Can be obstructive, restrictive, or mixed. Obstruction more commonly seen in chronic.
- BAL: Very sensitive but non-specific.
- BAL lymphocytosis (often greater than 50%) is helpful but non-specific. Can also see lymphocytosis in COP and NIP but not this high.
- Biopsy: Rarely done
- Antigen-specific immunoassays: very high false positive rate, role unclear.
- Corticosteroids, usually pred 60 1-2 weeks, then tapered over 2-4 weeks for acute/subacute cases
- Chronic: Longer course of prednisone
- Remove from environmental exposure ASAP
- Reversible if detected early and antigen exposure is eliminated
- Chronic: leads to fibrosis, which is NOT reversible.