12/13 PPMC Report: Granulomatosis with Polyangiitis

Thank you to Dr. Johr for joining us as a faculty expert to discuss a new diagnosis of granulomatosis with polyangiitis (GPA). The patient was a 19 year old previously healthy male who initially presented with variable upper respiratory and lower respiratory symptoms for a few months with multifocal pulmonary infiltrates refractory to antibiotics, who then developed glomerulonephritis with acute renal failure.

One important take-away from this case is to always think broadly about the differential without anchoring, and to make sure that your clinical decision-making takes your patient’s demographic and medical background into account. Our patient was a healthy 19 year old male who developed persistent otitis media, followed by persistent laryngitis and then lower respiratory symptoms with imaging demonstrating multifocal opacities. He also had constitutional symptoms and a urinalysis with large blood. He was treated at this point for community-acquired pneumonia — this diagnosis was likely an instinctive reaction to pulmonary consolidations and lower respiratory symptoms, but a previously healthy young male is not the typical host for CAP; furthermore, this diagnosis fails to take the patient’s other presenting signs and symptoms into account.

We discussed the differential for pulmonary-renal syndromes. It is not very long! While it is possible that the pulmonary and renal components demonstrate different disease processes, in most cases pulmonary-renal syndrome is secondary to ANCA-associated vasculitis (MPA, GPA, eGPA), Goodpasture’s (anti-glomerular basement membrane), or other rheumatologic conditions (SLE). Our patient’s clinical history of upper airway disease and his presentation with pulmonary-renal syndrome was clinically very strongly concerning for GPA, and his serologies were consistent with this diagnosis (positive anti-PR3 and c-ANCA).

“ANCA” stands for anti-neutrophil cytoplasmic antibody — these can be positive in a number of conditions, even IBD! Recently, identification of a specific anti-nuclear antibody (ie either anti-MPO or anti-PR3) has become increasingly clinically relevant. As we have discussed previously on this blog in our PAN case, vasculitis is inflammation of the vessels and is typically classified based on size of involved vessels. Small-vessel disease can be sub-categorized by disease mechanism into those caused by immune complex deposition, and those caused by presence of ANCA. Figure below from Jennette et al, Arthritis and Rheumatology.

PAN1

GPA is classically characterized by upper airway involvement and constitutional symptoms, and can commonly have renal involvement as well. This disease can also cause subglottis stenosis, which can be life-threatening and incredibly difficult to treat.  It is usually associated with positive anti-PR3 and c-ANCA.

Treatment strategy depends on severity and organ involvement, and also on the patient’s demographics and comorbidities. In general, induction therapy involves a combination of high dose glucocorticoids and either cyclophosphamide or rituximab. In severe cases, plasma exchange can also be used. Treatment also involves a maintenance phase.

References:

Jennette JC et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 013; 65:1.

 

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11/30 HUP Report: Polyarteritis Nodosa

Today we were joined by a world expert in vasculitis, Dr. Peter Merkel, to discuss an interesting case of a young female who presented with foot drop and necrotic skin lesions.

This constellation of symptoms can be caused by a few different disease entities, but we focused our discussion on vasculitides. Vasculitis is typically characterized by which size of vessel is affected by the inflammation process (Jennette et al, Arthritis Rheum):

PAN1.pngOur patient’s skin biopsy showed small/medium vessel vasculitis, and work up was notable for negative ANCA and other serologies. Clinically, this presentation was concerning for polyarteritis nodosa, which is a necrotizing vasculitis that typically affects medium-sized vessels. Common presenting symptoms include general malaise, myalgias/arthralgias; renal involvement is also very common, and skin lesions can be seen. Notably, pulmonary involvement is very uncommon. The following figure has been adapted from http://www.rheumaknowledgy.com.

PAN2.pngTreatment depends on severity of presentation and major organ involvement. Glucocorticoids are a cornerstone of treatment; combination immunosuppression may be necessary in severe cases, with many providers using a regimen of glucocorticoids and cyclophosphamide. Methotrexate, azathioprine, mycophenolate and rituximab have also been studied in this disease. Individual patient factors may need to be considered in treatment decisions too.

Data on treatments is limited since this is a very rare disease, and historically diagnosis criteria has changed making the patient population of interest more difficult to define. The study below (Gayraud et al, Arthritis and Rheumatism) retrospectively analyzed data from n=278 patients with PAN, MPA, or eGPA who had previously been enrolled in four different prospective studies looking at different treatment protocols. They found that in comparison to the general population (of France, where the study was conducted), patients with vasculitis had increased mortality – not surprisingly.

PAN2.pngThey also found that when stratified by severity of disease, patients with more severe disease who had been treated initially with a combination of glucocorticoids and cyclophosphamide had better outcomes than those treated with glucocorticoids alone.

PAN3

References:

Jennette JC et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.37715.

Gayraud M et al. Long-Term Followup of Polyarteritis Nodosa, Microscopic Polyangiitis, and Churg-Strauss Syndrome. Arthritis Rheum. 2001 Mar;44(3):666-675.

11/9 HUP Report – Rheumatoid Arthritis

Thank you to Dr. George for his expert insight in our discussion of a complicated case of rheumatoid arthritis. The patient presented post-partum with fairly symmetric inflammatory polyarthralgias and pleuritic pain.

We discussed a differential diagnosis combining these two primary presenting features of this patient’s clinical course, which included the following:

ra1The patient’s workup was notable for positive rheumatoid factor and CCP, which were supportive along with the clinical presentation of a diagnosis of rheumatoid arthritis. In patients with inflammatory arthritis, if they present with an accessible effusion it may be a good idea to perform arthrocentesis to ensure there is no concomitant crystal disease or infection. Some rheumatologists will also get baseline imaging.

The pathogenesis of rheumatoid arthritis is thought to be related to possibly underlying genetic susceptibility and environmental exposures that cause loss of self-tolerance in the host, and development of rheumatoid factor which can then incite inflammation and tissue damage. This is illustrated in the figure below from NEJM (full reference below).RA2Rheumatoid arthritis can be difficult to treat, and it can have systemic manifestations in addition to joint involvement. All patients with RA should be treated with DMARDs early in their course, with the goal of intervening to prevent irreversible damage. Methotrexate is commonly used. Anti-inflammatory medications and steroids can be used as adjunct therapy during times of high disease activity, but do not replace the role of DMARDs and should not be used alone! Several other medications have been studied in varying combinations; patient demographic factors must also be considered, particularly in females of child-bearing potential. Finally, all patients with this diagnosis should be referred to a rheumatologist!
References:

McInnes IB, Schett G. The Pathogenesis of Rheumatoid Arthritis. N Engl J Med 2011; 365:2205-2219December 8, 2011DOI: 10.1056/NEJMra1004965.

 

 

 

 

10/18 Presby report: inflammatory back pain

 

Thanks to Dr. Lan Chen for going through her approach to lower back pain and dropping some awesome rheum pearls!

Your physical exam provides important clues to the diagnosis of AS, its extra-articular manifestations, as well as other rheumatologic conditions

  • FABER/Patrick’s test: can suggest sacroiliitis
  • Lumbar spine exam (although SI inflammation/pain is more common than L-spine pain)
  • Nails: can show pitting suggestive of psoriatic arthritis
  • Skin: psoriatic plaques, erythema nodosum, pyoderma gangrenosum, keratoderma blenorrhagicum (reactive arthritis)
  • Eyes: uveitis
  • Tongue erosions (suggestive of reactive arthritis)

Recall some key features of inflammatory back pain:

  1. Onset of back discomfort before the age of 40 years;
  2. Insidious onset lasting more than 3 months;
  3. Improvement with exercise; No improvement with rest.
  4. Pain at rest or at night
  5. Profound morning stiffness

Presence of four out of five of those features has ~70% sensitivity and specificity for ankylosing spondylitis.

Imaging

Dedicated imaging of the sacroiliac joint is perhaps more useful than general spine or L-spine imaging, since sacroiliitis is more common than L-spine inflammation.

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CT scan: normal SI joint. Note the clean, linear joint space

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CT scan: sacroiliitis. Note the shaggy, narrowed joint space 

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MRI showing marrow edema adjacent to the joint space in a patient with sacroiliitis

In early disease (first few years of symptoms), only MRI is likely to be sensitive enough to pick up SI joint changes; as the disease progresses, CT becomes more sensitive (~5 years into disease course). X-rays are really only useful in advanced disease.

Treatment

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Zochling J, et al. Ann Rheum Dis 2006.

Additionally:

  • Ustekinumab and secukinumab are anti-IL23/IL17 biologics that can be used to treat AS
  • Apremilast is a PDE4 inhibitor that can also be used for AS

There are multiple causes of inflammatory back pain:

  • Primary ankylosing spondylitis
  • Psoriatic arthritis
  • Reactive arthritis
  • Enteropathic arthritis
    • Crohn’s disease
    • Ulcerative colitis
  • Juvenile ankylosing spondylitis
  • Undifferentiated spondyloarthropathies

Other rheum pearls

  • Obesity may be a risk factor for autoimmune disease
  • Gonococcal arthritis tends to more commonly affect upper extremity joints, while reactive arthritis tends to affect lower extremity joints

References

 

10/17 HUP Report – Scleroderma Renal Crisis

Today we were joined by faculty expert Dr. George to discuss a case of scleroderma renal crisis. We spent some time discussing hypertensive emergency, which was this patient’s initial presentation — that has been addressed in earlier blog posts so we will focus on the diagnosis of scleroderma renal crisis (SRC) in this post.

 

There are three major diagnostic considerations for scleroderma renal crisis in a patient with signs or symptoms of scleroderma:

  • abrupt onset of moderate/severe HTN (from increased plasma renin activity)
    • NOTE: approximately 10% of patients are normotensive when presenting with SRC, so do not completely dismiss this dx from your differential in a normotensive patient! They have a worse prognosis than hypertensive patients, possibly due to delayed recognition and treatment!
  • Acute kidney injury
  • Urinalysis is usually unremarkable, though may have a few cells/casts and mild proteinuria

Scleroderma renal crisis is thought to be caused by pathology in the renal vasculature, specifically intimal proliferation and thickening that leads to narrowing and obliteration of the vascular lumen. Some people suggest conceptualizing this as a similar pathophysiologic process to bilateral renal artery stenosis.

Risk Factors

  • Almost always occurs within 5 years of onset of scleroderma
  • Diffuse systemic sclerosis (much more common than limited)
  • Glucocorticoid use (especially doses >15mg prednisone daily)
  • Rapid progression of skin involvement
  • Positive RNA polymerase III antibody
  • NOT risk factors: pre-existing HTN, elevated Cr, or abnormal UA

Monitoring

In patients diagnosed with scleroderma, it is recommended to perform frequent BP checks (daily if high risk) and further workup if sustained increase in SBP >/20 or DBP >/ 10. They should also have urine dip and Cr checked every 3 months.

 

Treatment

ACE Inhibitors are the mainstay of treatment in SRC. There have not been randomized controlled trials to support this treatment, but several observational studies noted improved outcomes. ACE Inhibitors should be initiated immediately, and usually captopril is used during inpatient treatment due to rapid effect and ability to titrate quickly.

All patients with SRC should be on lifelong ACE inhibitor therapy, even patients who present normotensive or those who go on to have improvement in renal function and HTN. Long acting formulations can be used for better adherence.

Many patients will require transient or permanent renal replacement therapy. Some will go on to get renal transplants, although other systemic manifestations of scleroderma can be contraindications. The grafts do not survive as well as in other indications for renal transplant.

 

 

8/24 (HUP) intern report: eosinophilia and migratory polyarthralgia

Late post from last week. Thanks to our excellent sub-I Juan Spinnato for presenting the case of an older man with subacute cough, dyspnea and polyarthralgias who was found to have a marked eosinophilia, and was ultimately diagnosed with a large intrahepatic mass, now favored to be cholangiocarcinoma 😦

Pearls

  • Polyarthralgias have a huge differential, so certain features can help narrow your differential
    • Distribution: pattern (small vs large joints), symmetry, axial involvement
    • Extra-articular manifestations (rash, eye symptoms, muscle weakness)
    • Duration: <6 weeks is often viral, >6 weeks bears further investigation for other causes
    • Periodicity: intermittent (crystalline arthritis) vs constant
    • Demographics (gender, age, race, family hx)

 

We also talked about the utility of inflammatory markers!

Key points

  • What can increase or decrease the ESR?
    • Increase: infection, inflammation (duh), malignancy, trauma
    • Decrease: abnormally shaped RBCs (SCD, spherocytosis, etc), heart failure, extreme leukocytosis
  • There are underlying conditions that can ‘falsely‘ elevate the ESR more than expected
    • Elevate: older age (correction formula: ULN of reference range = age/2 for men and (age + 10)/2 for women), female gender, ESRD, obesity
  • Conditions that can cause a discrepancy between ESR and CRP
    • Elevated ESR, normal CRP
      • monoclonal immunoglobulins
      • SLE (felt to be because type I IFNs produced in SLE inhibit CRP synthesis by liver)
        • Elevated CRP in SLE should raise suspicion for underlying bacterial infection

References

Richie et al. Diagnostic Approach to Polyarticular Joint Pain. Am Fam Phys. 2003.

6/15/17 at HUP: an approach to weakness, HMG CoA reductase Abs

Rheumatologist extraordinaire Mike George was kind enough to help us through a case of a middle-aged woman with weakness who was ultimately diagnosed with a necrotizing myopathy due to HMG CoA reductase antibodies. Along the way we learned how to approach a patient with weakness:

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Take home pearls:

  1. Use a neuroanatomic approach to a patient with weakness
  2. Perform a good neuro exam (including reflexes) on any patient with weakness
  3. Endocrine and toxic/drug myopathies are the most common of any kind of myopathy (including inflammatory myopathies)

References

  1. Chawla J. Stepwise Approach to Myopathy in Systemic Disease. Frontiers in Neurology 2011.
  2. Mammen, A. 2016. Statin-Associated Autoimmune Myopathy. The New England Journal of Medicine. 374, 7 (2016), 664–669.