Lupus, TB, and IgG4

Motivation: Recently, I have heard increasing whispers about IgG4 related disease.  In the  list of diseases that are hard to diagnose with widely varying symptoms, long time residents like TB and lupus are being joined by IgG4.  Of course, I have yet to see a single patient with IgG4 related disease personally.  But, when mentioned, I do not know how to fend off the possibility.  So, how do patients with IgG4 typically present?

As way of background, IgG4 related disease has become the topic of much discussion only since 2001, when autoimmune pancreatitis related to IgG4 was first described.  Pathologically, IgG4 related disease is characterized by extensive IgG4+ plasma cell infiltration.

Paper: Zen, Y and Nakanuma, Y. "IgG4-Related Disease: A Cross-Sectional Study of 114 Cases" Am J. Surg. Pathol. (2010); 34: 1812.

Methods: Between 1990 and 2009, pathological samples with diffuse IgG4 plasma cell infiltration were retrieved from case files at Kanazawa University Hospital and affiliated hospitals in Japan.  Clinical features of patients meeting criteria were retrospectively reviewed from medical records.

Results: 
Location: Total of 114 patients with IgG4 related disorder were identified.  Location of disease is as follows:

• 23 patients (20.1%) with head and neck lesions - primarily salivary gland and lacrimal gland
• 16 patients (14.0%) with thoracic lesions found in lung, pleura, and breast
• 27 patients (23.6%) with hepatobiliary lesions in pancreas, bile duct, gallbladder, and liver
• 13 patients (11.4%) with retroperitoneal disease presenting with retroperitoneal fibrosis and aortitis
• 35 patients (30.7%) with diffuse systemic manifestations

Demographics: Median age of presentation is 64 with youngest aged 42.  Male and females were almost evenly distributed for the head and neck group.  On the other hand, >70% of the patients were male with thoracic lesions and >80% were male with hepatobiliary, retroperitoneal, and systemic presentations.

Associated Autoimmune Diseases: In the cohort, 22 patients had history of allergy while only 2 had a clinical history of autoimmune disease - one with sarcoidosis and one with rheumatoid arthritis.  Enlarged lymph nodes were found in 47 patients (41%) by physical and radiologic examination.

Serum Concentration of IgG4: IgG subset information was available in 58 patients.  Serum IgG4 was elevated in 50 of 58 patients (86%).  Serum levels of IgG4 were highest in patients with systemic and head & neck disease.

Lesion Features: Of the biopsied lesions, all except one lesion was macroscopic - could be identified by physical exam or by radiology.  When IgG4 related disease affected a solid organ, the pattern of infiltration was either diffuse or as mass-like lesion.

Malignancy: Of 114 patients, 3 patients in the systemic group presented with malignancy during follow-up: small cell carcinoma (1 year after IgG4 diagnosis), adenocarcinoma (2 years later), and B cell lymphoma (4 years later).

Discussion: What I take away from this cross-sectional description is that this oft invoked but little understood disease is very different from traditional auto-immune diseases.  IgG4 related disease can occur in just about any part of the body, but the likely presentation is a macroscopically visible diffusely infiltrative or mass-like lesion.  Besides testing for IgG subsets, there is little to distinguish it (at least in this survey) at first glance from neoplastic disease.  Importantly, the disease does not appear correlated with other auto-immune phenomenon such as lupus or rheumatoid arthritis or paraneoplastic disease.  I think that in the future, we will learn more about historical features, but for now, IgG4 related disease remains hard to diagnose with protean manifestations - just like lupus and TB.

MRI for C-spine

Motivation: An elderly man trips on ice and falls.  He complains of neck pain in the ED.  He gets a cervical spine CT, which is normal. He still complains of neck pain.  What do you do now?  I think that many doctors would follow different strategies.  Some would take off the cervical collar and provide ibuprofen.  Others would continue imaging with MRI.  What is the right approach?

As way of background, for cervical spine injury, potentially dangerous ligamentous injuries remain on the differential even after a negative CT.  What is less clear is the incidence of these injuries and the clinical significance of these findings.

Paper: Schoenfeld, A.J., Bono, C.M., McGuire, K.J. et. al. "Computed Tomography Alone versus Computed Tomography and Magnetic Resonance Imaging in the Identification of Occult Injuries to the Cervical Spine: A Meta-Analysis" J. Trauma. (2010); 68(1): 109.

Methods: Meta-analysis of prospective and retrospective studies of MRI after negative CT.  True positive MRI was defined as change in clinical management per clinician judgement.

Results:
Studies: Eleven studies were identified evaluating 1,550 blunt trauma patients evaluated initially by CT and then by MRI.  None of the trials were randomized controlled trials.

Abnormalities: Of the entire cohort, 194 MRI abnormalities were detected in 182 patients (12% of cohort) with negative CT scans.  Of these abnormalities, majority (86, 47% of abnormalities) were ligamentous injuries.  Other significant injuries detected were: degenerative changes (47, 24% of abnormalities),  cord contusion (16, 8.2% of changes), fracture (3, 1.5% of changes), and cord contusions (16, 8.2% of changes).

Clinical Outcomes: As a result of MRI, 84 patients (5% of cohort) required prolonged use of collar, and 12 patients (1% of cohort) required cervical stabilization.  In 86 patients (5.5% of patients), MRI findings were judged clinically insignificant.  For MRI, the pooled sensitivity was 100%, and the pooled specificity was 94%.

Discussion: This paper surprised me with the number of clinically significant injuries missed on CT scanning. About 1% of patients required operative intervention after an apparently normal CT scan.  Similarly, about 1% of patients had cervical cord contusions despite a negative CT scan.  What is not apparent from this paper though are the factors predictive of positive MRI findings with a negative CT scan.  In the absence of clear prospective data, I would think that persistent neck pain or any neurological findings calls for an MRI scan despite a negative CT scan.  So, in summary, if an elderly man continues to complain of neck pain even with a negative CT, I would recommend a cervical MRI.

Back Brace

Motivation: I have never worn body armor, but a thoracolumbar brace looks close to it.  I often see the full body brace clipped onto elderly women after a compression fracture of the spine from a fall, and I wonder if it actually does anything besides making for a closeted experience.  Although there are many practices in surgery without evidence, turns out that this idea has actually been tested in a single randomized trial.

Paper: Stadhouder, A., Buskens, E., Vergroeen, DA, et. al. "Nonoperative treatment of thoracic and lumba spine fractures: a prospective randomized study of different treatment options." J Orthop. Trauma (2009); 23: 588.

Methods: Randomized trial carried out in Amsterdam.  Patients younger than 80 with traumatic thoracic or lumbar compresssion fractures ( less than 50% disc height loss or 30% spinal canal stenosis) without neurological impairment were randomized to (1) physical therapy for 6 weeks, (2) removable brace for 6 weeks, or (3) plaster of paris cast for 6 or 12 weeks.  No single primary outcome pre-specified.  Parameters followed included radiographic improvement, pain measure, and disability index meaurd at 6 weeks, 12 weeks, 6 months, and 12 months.

Results:
Cohort: Total of 108 patient were randomized with 54.1% women with mean age of 45.  Baseline measurements such as gender distribution, age, and admission time were similar among groups.  Majority of patients had high-energy trauma.

Tolerability: For compression fractures, physical therapy was better tolerated than plaster of paris but not significantly different than brace therapy.  Brace therapy was also better tolerated than plaster of paris therapy.

Residual Pain: At long term follow-up (1 year later), visual analogue scale residual pain was significantly less for brace compared to plaster of paris therapy for 12 weeks (mean difference 19.0, CI: 1.87-36.2).  There was no difference between physical therapy and brace therapy or between brace therapy and cast for 6 weeks.

Disability Index: At long term follow-up, measure by Owestry Disability Index, brace therapy for 6 weeks was superior to physical therapy (mean difference 14.9, CI: 2.7-27.1) and cast for 12 weeks (mean difference 10.1, CI: 0.25-25.0) or 6 weeks.

Discussion: I think that this paper represents one of the many cases in medicine where an exploratory trial of limited power has been generalized to a wide population.  The patients in the trial were primarily in their 40s presenting after a high-impact accident.  These patients are clearly different than the elderly patients with osteoporotic compression fractures encountered in clinical practice.  Moreover, the trial itself suffers from several notable flaws with perhaps the lack of a pre-specified primary outcome being the most significant one.  Even for the significant outcomes, the confidence intervals are very wide.  While a brace makes pathophyiological sense for treating fractures, the treatment choice for compression fractures remains an area of uncertainty.