A case of relapsing polychondritis

From a case report and mini review in the American Journal of Medicine:

McAdam and the Damiani/Levine diagnostic criteria. 12 RPC is diagnosed if 3 of 6 clinical findings are present: 1) auricular chondritis; 2) nonerosive inflammatory arthritis; 3) nasal chondritis; 4) ocular inflammation, including conjunctivitis, keratitis, scleritis, episcleritis, or uveitis; 5) laryngotracheal chondritis; and 6) cochlear or vestibular damage presenting as sensorineural hearing loss, tinnitus, or vertigo. A diagnosis of RPC also can be made if a patient meets one of 6 criteria AND has compatible cartilage biopsy histology or meets 2 of 6 criteria AND improves clinically after receiving corticosteroids or dapsone. 2

RPC is a rare inflammatory disease with a peak age of onset between ages 40 and 50 years and an estimated incidence of 3.5 cases per million people per year. 3 Cases have been diagnosed across all racial groups. Men and women are equally affected. 3 RPC is defined by abrupt-onset inflammation of the cartilaginous ear, nose, joints, laryngotracheobronchial tree, or heart valves. The disease usually follows an indolent, relapsing-remitting course but may also present fulminantly and threaten vision and organ function. 4 …

Up to one-third of cases of RPC present prior to, during, or after another disease. 6 The most commonly associated syndrome is systemic vasculitis, followed by rheumatoid arthritis and systemic lupus erythematosus.

Thyroid acropachy: an unusual complication of Graves disease

From a recent published case report and mini-review:

The pathogenesis of acropachy is unknown, except for the anatomic location, in that it is probably similar to that of pretibial myxedema. It appears that TRAb molecules bind to the TSH receptors of fibroblasts present in the periosteum region and trigger an inflammatory response, producing cell proliferation and glycosaminoglycan deposition (7,8). The musculoskeletal manifestation is almost never seen without the remaining components of the triad of orbitopathy, dermopathy, and acropachy (9,10). Some studies suggest smoking is a predisposing factor for acropachy in GD patients (9).

In most cases, acropachy is asymptomatic, but the main clinical manifestations are digital clubbing, skin tightness with or without digital clubbing and usually with small-joint pain (in severe cases), soft tissue edema, and reactional periosteum, and skin alterations in fingers and nails may also be present (7). The disorder mostly affects the metacarpus phalangeal and proximal interphalangeal regions in the upper and lower limbs, especially the ankles and metatarsal phalangeal joints (11).

Check point inhibitor induced colitis

An emerging entity.

Should you get immunoglobulin levels on patients admitted with community acquired pneumonia?

From a recent study:

BACKGROUND: Immunodeficiency is an underrecognized risk factor for infections, such as community-acquired pneumonia (CAP).

OBJECTIVE: We evaluated patients admitted with CAP for humoral immunodeficiency.

DESIGN: Prospective cohort study.

SETTING: Inpatients

PATIENTS, INTERVENTION, AND MEASUREMENTS: We enrolled 100 consecutive patients admitted with a diagnosis of CAP from February 2017 to April 2017. Serum IgG, IgM, IgA, and IgE levels were obtained within the first 24 hours of admission. CURB-65 score and length of hospital stay were calculated. The Wilcoxon rank-sum test, Kruskal-Wallis test, and simple linear regression analysis were used in data analysis.

RESULTS: The prevalence of hypogammaglobinemia in patients with CAP was 38% (95% CI: 28.47% to 48.25%). Twenty-seven of 100 patients had IgG hypogammaglobinemia (median: 598 mg/dL, IQ range: 459-654), 23 of 100 had IgM hypogammaglobinemia (median: 38 mg/dL, IQ range: 25-43), and 6 of 100 had IgA hypogammaglobinemia (median: 36 mg/dL, IQ range: 18-50). The median hospital length of stay for patients with IgG hypogammaglobinemia was significantly higher when compared to patients with normal IgG levels (five days, IQ range [3-10] vs three days, IQ range [2-5], P = .0085). Fourteen patients underwent further immune evaluation, resulting in one diagnosis of multiple myeloma, three patients diagnosed with specific antibody deficiency, and one patient diagnosed with selective IgA deficiency.

CONCLUSION: There is a high prevalence of hypogammaglobinemia in patients hospitalized with CAP, with IgG and IgM being the most commonly affected classes. IgG hypogammaglobinemia was associated with an increased length of hospitalization. Screening immunoglobulin levels in CAP patients may also uncover underlying humoral immunodeficiency or immuno-proliferative disorders.

Autoimmune thyroid disease

Free full text review. From the conclusion:

The management of autoimmune thyroid disease continues to be revised by new research which includes the identification of new entities, such as IgG4-related thyroid disease and new drug-induced forms of thyroid disease; the development of novel small molecules capable of influencing mechanisms of autoimmunity; and more detailed knowledge of the risks versus benefits of thyroxine therapy in subclinical hypothyroidism.

Retroperitoneal fibrosis and its relationship to IgG 4 diseases

Review here.

Dealing with penicillin allergy

Free full text from Mayo Clinic Proceedings.

Non-gastrointestinal presentations of celiac disease

From a recent paper in the American Journal of Medicine:

Abstract

Purpose

The purpose of our study is to investigate the delay in diagnosis of patients with biopsy-proven celiac disease in those who present with gastrointestinal complaints vs nongastrointestinal complaints at our tertiary care center. Celiac disease is an autoimmune disorder that affects approximately 1% of the population worldwide. Celiac disease can have variable clinical presentations; it can be characterized by predominately gastrointestinal symptoms, or it may present without any gastrointestinal symptoms.

Methods

We retrospectively reviewed the charts of 687 adult patients who carried the diagnosis of celiac disease. Patients included had biopsy-proven celiac disease and were categorized based on presence or absence of gastrointestinal symptoms prior to their diagnosis.

Results

There were 101 patients with biopsy-proven celiac disease that met inclusion criteria. Fifty-two patients presented with gastrointestinal symptoms and 49 had nongastrointestinal complaints. Results from Mann-Whitney statistical analysis showed a median delay in diagnosis of 2.3 months for the gastrointestinal symptoms group and 42 months for the nongastrointestinal group (P less than .001); 43.2% of patients with nongastrointestinal symptoms had abnormal thyroid-stimulating hormone, as opposed to 15.5% in the gastrointestinal symptom group (P = .004). Of patients with nongastrointestinal symptoms, 69.4% had anemia, compared with 11.5% of the gastrointestinal symptom group (P less than .001). The majority of patients in the nongastrointestinal symptom group, 68%, were noted to have abnormal bone density scans, compared with 41% in the gastrointestinal symptom group. No sex differences were noted on chi-squared analysis between the 2 groups (P = .997).

Conclusions

Although there is growing awareness of celiac disease, the delay in diagnosis for patients without gastrointestinal symptoms remains prolonged, with an average delay of 3.5 years.

Clinical Significance

There is a mean delay in the diagnosis of celiac disease of 3.5 years in patients who present with nongastrointestinal symptoms.

Specifically, patients with thyroid abnormalities, anemia, or bone mineral density loss should be screened for celiac disease.

Celiac disease is an autoimmune disorder that affects approximately 1% of the population worldwide.1 As many as 6 of 7 cases of celiac disease remain undiagnosed.2 This discrepancy falls in line with the widely accepted “celiac iceberg” concept and may be due to the fact that patients have variable presentations of celiac disease. Manifestations of celiac disease range from typical gastrointestinal complaints characterized by malabsorption and diarrhea, to more silent forms in patients without overt gastrointestinal complaints. Nongastrointestinal presentations may include anemia, thyroid dysfunction, osteoporosis, liver function test abnormalities, and skin manifestations such as dermatitis herpetiformis. The variable presentations create a clinical challenge to physicians in reaching an early diagnosis. As a result, delay in diagnosis is not uncommon and does not go without consequence. Undiagnosed celiac disease can lead to osteoporotic fractures, infertility, unnecessary surgical procedures including bowel resection, and malignancy.1 As the majority of cases of celiac disease can be treated with a strict gluten-free diet alone, adherence to this diet can reverse the risk for adverse clinical outcomes.

Exhaled nitric oxide to guide management of asthma

The conclusion from a recent Cochrane review:

AUTHORS' CONCLUSIONS:

With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings, and taking into account different FeNO cutoffs are required.

Narcolepsy: an autoimmune disease?

From a recent review:

Recent findings
Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Recent studies suggest both humoral and cellular immune responses in the disease development.

Summary
Narcolepsy is a severe sleep disorder, in which neurons producing orexin/hypocretin in the hypothalamus are destroyed. The core symptoms of narcolepsy are debilitating, extreme sleepiness, cataplexy, and abnormalities in the structure of sleep. Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Importantly, the highest environmental risk is seen with influenza-A infection and immunization. However, how the cells are destroyed is currently unknown. In this review we summarize the disease symptoms, and focus on the immunological findings in narcolepsy. We also discuss the environmental and genetic risk factors as well as propose a model for disease development.

Dealing with drug allergy

Drug Allergy: An Updated Practice Parameter is an official document promulgated by a collaboration of three professional societies. Although it is a bit dated it is the latest such edition written by the collaboration. Moreover, for penicillin allergy an update was published in Mayo Clinic Proceedings only months ago. The Mayo update generally follows the recommendations of this document. Below are some key points.

The overall classification of drug induced disease encompasses all types of adverse reactions, not just allergic reactions.

From the document:

ADRs are broadly categorized into predictable (type A) and unpredictable (type B) reactions. Predictable reactions are usually dose dependent, are related to the known pharmacologic actions of the drug…

Unpredictable reactions are generally dose independent, are unrelated to the pharmacologic actions of the drug, and occur only in susceptible individuals. Unpredictable reactions are subdivided into drug intolerance, drug idiosyncrasy, drug allergy, and pseudoallergic reactions.

Allergic reactions are defined as immunologic reactions. Although the Gell-Coombs classification remains the framework for thinking about allergic reactions, the current classification has been extended beyond that.

Categories outside the C-G classification include these below. Form the paper:

Hypersensitivity vasculitis Cutaneous or visceral vasculitis Hydralazine, penicillamine, propylthiouracil

DRESS Cutaneous, fever, eosinophilia, hepatic dysfunction, lymphadenopathy Anticonvulsants, sulfonamides, minocycline, allopurinol

Pulmonary drug hypersensitivity Pneumonitis, fibrosis Nitrofurantoin, bleomycin, methotrexate

Systemic drug-induced lupus erythematosus Arthralgias, myalgias, fever, malaise Hydralazine, procainamide, isoniazid

Cutaneous drug-induced lupus erythematosus Erythematous/scaly plaques in photodistribution Hydrochlorothiazide, calcium channel blockers, ACE inhibitors

Drug-induced granulomatous disease Churg-Strauss syndrome, Wegener's granulomatosis Propylthiouracil, leukotriene modifiers

Immunologic hepatitis Hepatitis, cholestatic jaundice Para-aminosalicylic acid, sulfonamides, phenothiazines

Blistering disorders Erythema multiforme, SJS, TEN Sulfonamides, cephalosporins, imidazole anticonvulsants, NSAIDs

Serum sickness–like reactions Erythema multiforme, arthralgias Cefaclor, cefprozil

Immunologic nephropathy Interstitial nephritis, membranous glomerulonephritis Penicillin, sulfonamides, gold, penicillamine, allopurinol

It should be mentioned that some of the categories listed above are poorly understood and may not represent purely immunologic mechanisms.

What is “desensitization?”

More from the paper:

What has often been referred to as drug desensitization is more appropriately described in this parameter as a temporary induction of drug tolerance. Drug tolerance is defined as a state in which a patient with a drug allergy will tolerate a drug without an adverse reaction. Drug tolerance does not indicate either a permanent state of tolerance or that the mechanism involved was immunologic tolerance. Induction of drug tolerance procedures modify a patient's response to a drug to temporarily allow treatment with it safely. They are indicated only in situations where an alternate non–cross-reacting medication cannot be used. Induction of drug tolerance can involve IgE immune mechanisms, non-IgE immune mechanisms, pharmacologic mechanisms, and undefined mechanisms ( Table 2 ). All procedures to induce drug tolerance involve administration of incremental doses of the drug. Through various mechanisms, these procedures induce a temporary state of tolerance to the drug, which is maintained only as long as the patient continues to take the specific drug.

Remember that this technique is recommend only when there is no reasonable alternative, and it doesn’t induce permanent tolerance.

There is also the idea of graded challenge, which is different from tolerance induction (desensitization). Graded challenge is essentially the administration of a test dose.

Remember this, too, from the paper:

Graded challenge (or induction of drug tolerance) should almost never be performed if the reaction history is consistent with a severe non–IgE-mediated reaction, such as SJS, TEN, interstitial nephritis, hepatitis, or hemolytic anemia.

The recommendations for dealing with beta lactam type I allergy are complex

If the allergic history is that of an anaphylactoid reaction there is almost no avoiding the use of special techniques such as skin testing or tolerance induction, were one to strictly follow the document recommendations. Clinical rules cannot assure safe administration of an antibiotic. Consider assessment of side chain similarity for the assessment of safety of cephalosporin administration, for example. Although side chain assessment can be of help in the assessment of risk, in the document there is no recommendation for using it as an assurance of safety. On the other hand, in a couple of cases it can be used to mandate avoidance (such as the use of aztreonam in a patient with an anaphylactoid reaction to ceftazidime).

The application of the special techniques of skin testing, test dosing and tolerance induction is complex and has many contingencies noted in the document and therefore requires expertise.

Practical aspects for the clinician in dealing with type 1 beta lactam allergy

Despite the complexities noted above one can be informed by data on absolute risk. For example, according to the Mayo paper, cross-reactivity between PCN and carbapenems is likely less than 1%, with similar risk for aztreonam. What should one do, for example, when confronted with a patient in septic shock with concern for pseudomonas and ESBL producing bacteria? Considering a mortality increase of 5-10% per hour of non coverage, can you get an allergist on site and skin testing done in time or does the risk of delay exceed a less than 1% chance of a reaction from a carbapenem?

Autoimmune hemolytic anemia

Case report and review.

Insulin autoimmune syndrome aka Hirata disease

It’s caused by spontaneous development of insulin antibodies (no prior exposure to insulin). If that’s the case why does it cause hypoglycemia and not just hyperglycemia? From a review:

Although the precise mechanism for hypoglycemia in IAS is unknown, the most widely accepted hypothesis is a mismatch between blood glucose and free insulin concentration, secondary to the binding and release of secreted insulin by autoantibodies.7 Following a meal or oral glucose load, glucose concentration in the bloodstream rises, providing a stimulus for insulin secretion. Autoantibodies bind to these insulin molecules, rendering them unavailable to exert their effects. The resultant hyperglycemia not only promotes further insulin release, but may also explain the increased hemoglobin A1c often seen in IAS patients.6 As glucose concentration eventually falls, insulin secretion also subsides, and the total insulin level decreases. Insulin molecules spontaneously dissociate from the autoantibodies at this time, giving rise to a raised free insulin level inappropriate for the glucose concentration, evoking hypoglycemia.7 Insulin autoantibodies with a high binding capacity and a low affinity are more likely to bring about hypoglycemic symptoms.10 Medications containing a sulfhydryl group have been proposed to induce autoantibody formation by interacting with the disulfide bonds of the insulin molecule and augmenting its immunogenicity;11 however, the true underlying pathophysiology remains unclear at this time. Rarely, the co-existence of both insulin autoantibodies and insulin receptor autoantibodies within the same patient has been described.12

Eosinophilic granulomatosis with polyangiitis (EGPA) aka Churg-Strauss syndrome: clinical presentations

This small case series contains a number of pearls. The typical presentation was that of neuropathic symptoms, usually in the lower extremity (mononeuritis and usually multiplex) in a patient with a history of asthma for years. Most had a rash resembling Janeway lesions. Consistent with what we have traditionally been taught, only about half had a positive ANCA, mainly P. Think of it if your asthmatic patient inexplicably begins complaining of foot pain or numbness.

The Coombs test: some things you need to know

A nice free full text review in the Archives of Pathology and Laboratory Medicine.

Update on the clinical and pathologic aspects of ANCA diseases

Free full text review.

Multiple clinical manifestations of IgG4 related disease (IgG4-RD)

Here are some key issues addressed in a recent review.

What are some of the IgG4 related diseases?

These may coexist in the same patient:

Autoimmune pancreatitis type 1

Mikulicz disease (salivary gland infiltration)

Constrictive pericarditis

Coronary artery aneurysm

Inflammatory abdominal aortic aneurysm (and the related condition retroperitoneal fibrosis)

Sclerosing mediastinitis

Riedel's thyroiditis (and other forms of thyroid involvement)

Sclerosing mastitis

Pulmonary mass or interstitial disease

Hypophysitis

Prostatitis

Lymphadenopathy (Castleman like and other forms)

Tubulointerstitial nephritis

Sclerosing cholangitis (which differs in some features from primary sclerosing cholangitis)

How is IgG4-RD diagnosed?

This has been in a state of some controversy and flux. From the article:

According to an international symposium held in 2011, the diagnosis of IgG4-RD requires both an appropriate histological appearance and increased numbers of IgG4-positive plasma cells (or an elevated IgG4:IgG ratio) in tissue...

In 2011, an “All Japan IgG4 Team,” with the aim to draft comprehensive diagnostic criteria for IgG4-RD 51 ( Table 3 ), proposed three major items 51 69 (1) single or multiple organs involved with diffuse or localized swelling, masses, nodules, and/or hypertrophic lesions; (2) elevated serum IgG4 levels (greater than or equal to 135 mg/dL); and (3) histopathologic features that include marked lymphocytic and plasma cell infiltration and fibrosis, with IgG4-positive plasma cell infiltration (IgG4/IgG-positive cell ratio of greater than or equal to 40% and IgG4-positive plasma cells exceeding 10/HPF). Based on these criteria, patients can be classified into the categories of definite, probable, or possible IgG4-RD.

How do autoimmune pancreatitis (AP) types 1 and 2 differ?

Age: older onset (6^th decade) typical of type 1

Gender: male predominance in type 1, not 2

Relationship to IgG4: present in type 1, not clearly present in 2

Histology: lymphoplasmacytic sclerosing pancreatitis in type 1, idiopathic duct centric pancreatitis in 2

Abdominal pain: common in type 2, not in 1

Other organ involvement common in 1, not 2

Steroid responsiveness characterizes both types but type 1 is more prone to relapse.

IgG-4 related disease overview

Here is an overview from Disease of the Month. IgG-4 diseases include one of the two types of autoimmune pancreatitis and several other conditions:

Immunoglobulin G4-related disease is a rare but increasingly recognized multisystem entity characterized by lymphoplasmacytic tissue infiltration...Related manifestations of this disease include Reidel’s thyroiditis, chronic sclerosing dacryoadenitis, autoimmune pancreatitis (type 1 AIP), retroperitoneal fibrosis, and tubulointerstitial nephritis. Usually occurring in older men, the diagnosis is primarily based upon finding of histopahtologic changes..

Cystic lung disease as a manifestation of Sjogren Syndrome

From a recent paper in Chest:

Methods Eighty-four patients with primary or secondary SS and chest imaging, chest radiograph, or CT scan were retrospectively evaluated for CLD. Thirteen patients with cysts were found. Baseline characteristics of all patients were collected. A multivariate logistic regression model was used to look for predictors of CLD in patients with CT scan. Additional imaging, SS activity, and complications from CLD and SS were collected for the patients with cysts.

Results CLD had a frequency of 15.4% for all patients with chest imaging. Not all cysts were evident on radiography, and CLD frequency was 30.9% for the patients with chest CT scan. Six patients had cysts without other radiographic findings. CLD was associated with older age (OR, 1.1; 95% CI, 1.0-1.16), a diagnosis of secondary SS (OR, 12.1; 95% CI, 1.12-130.4), and seropositivity for anti-SS-related antigen A/Ro autoantibodies (OR, 26.9; 95% CI, 1.44-93.61). There was no radiologic progression of CLD for 12 patients after a 4-year median follow-up. Lung function did not exhibit temporal worsening. CLD did not correlate with a specific pattern in pulmonary function testing. Two patients had secondary infectious complications of the cysts.

And here is a nice general review of cystic lung disease and its various associations.

Genetics of eosiniphilic esophagitis

This is reviewed in a recent paper. Though not inherited in a simple Mendelian fashion it is a disease of genetic predisposition. This results in considerable overlap with atopic conditions. Some key points:

EoE is a complex genetic disease. Five susceptibility loci have been identified to date.

Three of the EoE predisposition loci are shared across other atopic phenotypes; the remaining two appear to be specific to EoE

The effect sizes of the shared loci are more significant in EoE which may facilitate the characterization of the loci and development of novel therapy.