Acute Rheumatic Fever

Today, we talked about the very interesting case of a middle-aged man who presented with acute migrating oligoarthritis, found to be febrile with an inflammatory synovial fluid and elevated ASO titers consistent with acute rheumatic fever!


Clinical Pearls

  • Nonsuppurative manifestations of GAS infection include acute rheumatic fever (ARF), acute GN, and Scarlet fever.
  • Use the modified Jones Criteria to help you diagnose ARF and treat early if high suspicion for the disease (do not wait for titers to come back).
  • Late complications of ARF include rheumatic heart disease (10-20 years after infection) and Jaccoud arthropathy.
  • Treatment of ARF involves NSAIDs for arthritis, PCN G IM x 1 dose for acute presentation and then monthly for prophylaxis, and patient education about oral hygiene to prevent endocarditis and need for prophylaxis before invasive procedures.

Differential diagnosis for a migratory arthritis

  • Rheumatic fever
  • Infective endocarditis
  • Vasculitis (IgA, cryo, ANCA associated)
  • SLE 
  • Acute leukemia
  • Serum sickness
  • Viral arthritis
  • Bacteremia (staph, strep, mening/gonococcal)
  • Pulmonary infections (mycoplasma, histoplasma)
  • Lyme
  • Whipple’s

Nonsuppurative complications of GAS infection

  • ARF
  • Scarlet fever
  • Acute GN

Rheumatic fever 

  • Nonsuppurative sequela that occurs 2-4 weeks after GAS pharyngitis
  • Epi
    • More common in children 5-15 years of age
    • More common in resource limited settings
  • Pathogenesis:
    • Poorly understood, ?molecular mimicry
  • Clinical manifestations:
    • Two primary manifestations of disease

Two manifestations of ARF

(Table above from UpToDate)

  • Late sequelae
    • Rheumatic heart disease (10-20 years after infection), primary involves the mitral valve >aortic valve.
      • Leading cause of cardiovascular death in the first 5 decades of life in resource limited settings
    • Jaccoud arthropathy
  • Diagnosis:
    • Revised Jones criteria (joint and cardiac manifestations can only be counted once).
      • Major
        • Carditis and valvulitis (clinical or subclinical) – 50-70%
          • Usually pancarditis. Valvulitis especially of mitral and aortic valves, shown as regurg on echo.
          • Carey Coombs murmur: short mid-diastolic murmur heard loudest at the apex
        • Arthritis (migratory, involving large joints) – 35-66%, earliest symptom
          • Several joints affected in quick succession, each inflamed for a day or two to one week. Most common are knees, ankles, elbows, and wrists.
        • CNS involvement (Sydenham chorea) – 10-30%
        • Subcutaneous nodules – 0-10%
        • Erythema marginatum – <6% 
      • Minor
        • Arthralgia
        • Fever >38.5
        • Elevated acute phase reactants (ESR, CRP)
        • Prolonged PR interval on EKG
      • Diagnosis requires evidence of prior GAS infection plus:
        • 2 major OR
        • 1 major + 2 minor criteria OR
        • 3 minor criteria (only if patient has history of prior episode of ARF)
      • In a high prevalence setting, slightly modified criteria are used.
    • Labs:
      • Prior GAS infection through either
        • Throat culture
        • Positive rapid strep antigen test
        • Elevated or rising ASO titers
      • Treatment
        • Goals
          • Symptomatic relief of acute disease manifestations
            • Arthritis: NSAIDs
            • Carditis: if severe, heart failure treatments
          • Eradication of GAS
            • IM PCN G benzathine x 1
            • Contacts (throat culture test and treat if positive)
          • Ppx against future GAS infection to prevent progression of cardiac disease
            • PCN G IM once a month
            • For 5 years or until 21 years of age (whichever is longer)
            • If ARF with carditis and residual heart disease
              • 10 years or until 40 years, sometimes even lifelong
            • Education
              • Oral health
              • Ppx before any invasive procedures

On rhabdo and myopathies – 10/9/18

Thanks to Cameron and Adam for presenting the case of a middle aged man with no significant PMH who presented with diffuse myalgias and chronic progressive proximal muscle weakness, found to have a CK >12k and EMG findings concerning for an inflammatory myopathy, awaiting muscle bx for diagnosis.


Clinical Pearls

  • Rhabdomyolysis literally means dissolution of skeletal muscle and has a broad differential outside of the typical traumatic or exertional processes associated with it see below).
  • The four main inflammatory myopathies are dermatomyositis, polymyositis, inclusion body myositis, and necrotizing autoimmune myositis.
  • Polymyositis is rare and a diagnosis of exclusion after the other three main inflammatory myopathies have been investigated.
  • Overall, the prognosis of inflammatory myopathies is good with appropriate treatment.  The exception is inclusion body myositis which is a progressive disorder without any effective therapy.
  • Pigment nephropathy can occur with rhabdo regardless of the underlying etiology especially in patients with CK >5000.  Aggressive IV hydration to lower CK levels is important to reduce the risk of kidney injury.

Rhabdomyolysis:

DDx:

  • Traumatic
    • Crush injuries, surgery, prolonged compression from immobility or coma
  • Non-traumatic
    • Exertional:
      • Normal muscle: strenuous exercise, heat stroke, seizures, hyperkinetic states
      • Abnormal muscle: metabolic myopathies, mitochondrial myopathies, malignant hyperthermia, NMS
    • Non-exertional
      • Alcoholism
      • Drugs and toxins: lipid-lowering drugs (fibrates, statins), alcohol, heroin, cocaine, meth, colchicine
      • Infections: influenza, coxsackie, EBV, HIV, legionella
      • Electrolyte abnormalities: hypokalemia, hypophosphatemia, hypocalcemia
      • Endocrinopathies: DKA, HHS, hypothyroidism, vitamin D deficiency
      • Inflammatory myopathies (rare)
      • Paraneoplastic
      • Miscellaneous

Inflammatory myopathies

Largest group of potentially treatable myopathies in children and adults.

  • Four subtypes: distinguishing which process is important because each subtype has a different prognosis and response to therapy
    • DM
      • Anti-Mi-2, anti-MDA-5, anti-TIF-1, anti-NXP-2
    • PM
      • Rare, often misdiagnosed
      • Dx of exclusion
    • Necrotizing autoimmune myositis
      • More common than PM
      • Occurs alone or after viral infections or in association with cancer, CTD, or post-statin
      • Anti-SRP or anti-HMGCR
      • Highest CK level
    • Inclusion body myositis
      • Most common in people >50
      • 7.9 cases/million in the US
      • Distal muscles impacted first
      • Facial muscles impacted
      • Muscle atrophy occurs earlier than in others
      • Extramuscular manifestations are uncommon
      • Dysphagia occurs in >50%
      • Muscle atrophy is common
      • Lowest CK level
  • Up to 30% of patients with DM or PM have a constellation of clinical findings termed “antisynthetase syndrome”
    • Acute disease onset
    • Constitutional symptoms (fever, weight loss)
    • Myositis
    • Raynaud’s
    • Mechanic’s hands
    • Non-erosive arthritis
    • ILD
    • Labs show antibodies to tRNA synthetase enzymes (anti-Jo-1)
  • Extramuscular manifestations
    • systemic symptoms
    • cardiac arrhythmias or ventricular dysfunction
    • pulmonary complications (ILD)

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Table above adapted from this and this review article by NEJM.

Lymphocytic hypophysitis – 10/3/18

Thanks to Sahar for presenting the interesting case of a middle-aged woman with metastatic melanoma recently started on ipilimumab who presented with a headache and fatigue, found to have hypothyroidism and adrenal insufficiency with work up consistent with hypopituitarism related to an adverse effect of ipilimumab: lymphocytic hypophysitis!


Clinical Pearls

  • Remember that adrenal insufficiency and hypothyroidism are causes of elevated ADH levels.
  • Red flags for obtaining head imaging for headache include age >55, sudden onset, positional, onset after trauma or exercise, fever, focal neuro findings, and immunosuppression.
  • Pituitary adenomas can have three manifestations: mass effect, hormonal hypersecretion, and hypopituitarism.  When imaging shows a pituitary mass, your work up should address each of these categories.
  • The most sensitive test to assess hypothalamic-pituitary access function is LH/FSH!
  • Immunotherapies are commonly associated with a flare of autoimmune diseases.  A more rare side effect of CTLA-4 inhibitors (like ipilimumab) is lymphocytic hypophysitis (inflammation of the pituitary gland)
    • This condition commonly presents with headache out of proportion to neurologic findings and preferential decline in ACTH and TSH though other hormones can also be impacted.
  • For hypopituitarism, remember to always treat adrenal insufficiency first before replacing thyroid hormone.  Failure to do so can precipitate adrenal crisis!

Indications for imaging a patient with headache:

  • Age >55
  • Sudden onset
  • Worse with lying down or wakes patient from sleep
  • Rapid onset after trauma or exercise
  • Fever
  • Focal neurologic findings
  • New headache in immunosuppressed patient

Pituitary adenoma:

  • Evaluate for the following
    • Mass effect: visual field deficit, headache
    • Hormonal hypersecretion
      • Prolactin ⇒ galactorrhea, amenorrhea, infertility
      • GH ⇒ Acromegaly
      • TSH ⇒ hyperthyroidism
      • ACTH ⇒ Cushing disease
      • ADH ⇒ SIADH
    • Hyposecretion:

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Hypophysitis:

  • Inflammation of the pituitary
  • Four categories based on histologic findings:
    • Lymphocytic
      • Most common form
      • Seen in late pregnancy and post-partum period
      • Also associated with ipilimumab as our patient here!
    • Granulomatous
      • Idiopathic or secondary to GPA, sarcoid, TB
    • Plasmacytic (IgG4-related)
    • Xanthomatous (most rare)
  • Clinical presentation
    • Headache out of proportion to exam findings
    • Preferential decrease in ACTH and TSH ⇒ adrenal insufficiency and hypothyroidism
  • Prognosis:
    • Pituitary size eventually normalizes but pituitary loss of function is often permanent.

Hyponatremia:

Lastly, refer to this algorithm from our recent morning report to help you think through hyponatremia.

Angioedema 9/11/2018

Today Arthur presented a case of a young woman with a personal and family history of facial swelling presenting with acute onset periorbital and scalp swelling, in setting of recent hair-dye exposure. No urticaria or pruritus on presentation but she did have acute pruritus after exposure to the hair-dye. She responded quickly to benadryl and steroids. The final diagnosis is allergic angioedema.

What is angioedema? It is a non-pitting swelling of the deep/subcutaneous tissues.

Angioedema

(Image adapted to JAMA)

Pathophysiology of angioedema

  • Mast cell mediated (most common)
    • Examples: Food allergies, insect stings
    • IgE -> Mast Cells -> inflammatory response
      • BeE, FoodiE = IgE
    • Findings:
      • Flushing
      • Urticaria
      • Generalized pruritus
      • +/- bronchospasm, throat tightness, hypotension
    • Onset: Minutes after exposure, develop over the next few hours
    • Recovery: 24-48 hours
    • Anaphylaxis = life threatening systemic reaction which is a severe manifestation of an allergic reaction. Angioedema is a finding.
    • Management: IM Epi is FIRST LINE, 0.3 – 0.5mg IM, repeat Q5-15min PRN. Everything else (steroids, benadryl, anti-histamines) are adjuvant only. Get that IM Epi stat.
  • Bradykinin mediated
    • Examples: Acquired angioedema (AAE, associated with underlying malignancy or autoimmune conditions), RAAS-blocker angio edema (RAE, African Americans are 3x likely vs Whites), hereditary angioedema (HAE, autosomal dominant mode of inheritance)
    • Findings:
      • Absent urticaria/pruritus, bronchospasm.
      • Minimal skin findings but can have swelling without urticaria.
    • Onset: More prolonged course, can develop over 24-36 hours
    • Recovery: 2-4 days
    • Management: depends
  • Histamine/Unclear: Seen in idiopathic angioedema (IAE)

Angioedema algorithm

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HAE Management

  • C1 Inh concentrate (takes a while to obtain)
  • Icatibant (synthetic bradykinin receptor antagonist)
  • Ecallantide (recombinant plasma kallikrein inhibitor)
  • FFP (fastest to get!)
  • Supportive care, airway monitoring

Still’s Disease – 9/10/18

Thanks to Becky Lee yet again for presenting an interesting case of a young woman presenting with acute onset of fever and polyarthritis, found to have a history of similar episodes in the past together with a rash concerning for Still’s disease!


Clinical Pearls

  • 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.

Acute polyarthritis (>5 joints involved):

Remember that for rheumatologic disorders, timing, symmetry, and number of joints involved is crucial to coming up with a differential diagnosis.  So for our patient with acute polyarthritis, consider the following:

  • Infection
    • Viral: hepatitis, HIV, parvovirus B19
    • Spontaneous bacterial endocarditis
  • Rheumatologic:
    • Rheumatoid arthritis
    • Reactive arthritis
    • SLE
    • Dermatomyositis
  • Vasculitis
    • PAN
  • Drug reactions
  • Auto-inflammatory or disease of the innate immune system (as opposed to autoimmune or diseases of the adaptive immune system):
    • Periodic fever syndromes (TRAPS, PFAPA, hyper-IgD syndrome)
    • Still’s disease
  • Schnitzler’s syndrome – chronic urticaria associated with a monoclonal gammopathy (usually IgM kappa)
  • Sweet syndrome – painful skin lesions
  • Sarcoid
  • Kikuchi disease – cervical LAD and fever (necrotizing lymphadenitis)
  • HLH/Macrophage activation syndrome – leukopenia and thrombocytopenia, elevated triglycerides, low fibrinogen and haptoglobin

Still’s disease:

  • 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.
  • Clinical features ⇒ Yamaguchi criteria (need 5 total with  > 2 major)
    • Major criteria:
      • Daily fevers to 39
      • Arthritis >2 weeks
      • Non-pruritic salmon-colored macular/maculopapular rash on trunk or extremities (though cases of pruritic rash have also been reported)
      • ↑ WBC >10k, >80% neutrophils
    • Minor
      • Sore throat
      • LAD and/or splenomegaly
      • ↑ AST, ALT, or LDH
      • Negative ANA/RF
  • Treatment
    • Mild: NSAIDs
    • Moderate: NSAIDs + DMARDs
    • Severe: NSAIDs + DMARDs (IL1 receptor antagonists like anakinra appear to be more helpful than TNF inhibitors especially in sJIA)
  • Prognosis:
    • Overall good prognosis
    • Disease can be limited to one episode or recurrent over time
    • Poor prognostic indicators:
      • Hip and shoulder involvement
      • Erosive polyarthritis at initial diagnosis
  • Complications
    • Macrophage activation syndrome (ie HLH) can occur in 15% of cases
    • DIC
    • TTP
    • Diffuse alveolar hemorrhage
    • Pulmonary HTN
    • Aseptic meningitis

References: 

Great recent review article on Still’s disease (AOSD Review) and this prior post on our blog!

Inflammatory Bowel Disease – 7/31/18

Thanks to Connie for presenting a case of a young man with chronic bloody diarrhea, abdominal pain, and fever, found to have a new diagnosis of severe Ulcerative Colitis.


Clinical Pearls

  • Acute diarrhea requires work up in anyone >65, immunocompromised, blood in stools, fever, severe abdominal pain, recent antibiotics, known or suspected IBD, risky jobs like food handler, or recent travel.
  • Fecal calprotectin can help distinguish inflammatory from non-inflammatory diarrhea and is a more sensitive and specific marker than fecal leukocytes.
  • 5-ASA based drugs are generally more effective in the colon so their primary role is in the treatment of Ulcerative Colitis or Crohn’s Colitis.

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Disease severity in IBD:

  • Mild: <4 stools/day, no systemic toxicity
  • Moderate: 4-6 stools/day, no systemic toxicity
  • Severe: >6 stools per day, systemic toxicity
  • Fulminant: >10 BMs per day, continuous bleed, systemic toxicity

Key distinctions between UC and CD:

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Items in red in the table above correlate with disease activity.

Before initiating immunosuppression:

  • Check PPD/quantiferon
  • Hepatitis serologies
  • Administer routine live vaccines
  • Check TPMT level (to assess phenotype for bone marrow suppression secondary to 6MP).  If TPMT level low, do not give 6MP!

Hereditary angioedema – 1/10/18

Epidemiology

  • Autosomal dominant – look for a positive family history
  • Usually diagnosed early in life

Mediators

  • Caused by elevations in bradykinin
  • No effect by histamine or mast cells

Clinical Presentation

  • Recurrent angioedema without hives or pruritis
  • Skin and GI tract most commonly affected
  • Colicky abdominal pain of unexplained etiology
  • Hypokalemia due to bradykinin elevation leading to high levels of ACE which activate the RAA system

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Treatment

  • Usually self-limited within 2-5 days
  • Can use FFP as FFP contained C1 inhibitor and ACE
  • Can use C1 inhibitor analogues, kallikrein antagonists, or bradykinin receptor antagonists for treatment if concern for rapidly progressive angioedema