ANCA testing in eosinophilic granulomatosis with polyangiitis (EGPA)

 

The American Journal of Respiratory and Critical Care Medicine published a consensus statement on the use of ANCA testing in patients with eosinophilic granulomatosis with polyangiitis  (EGPA,formerly Churg Strauss syndrome).  The article serves is a helpful update and review on some aspects of EGPA.

First some Basics about the ANCA test. The two main types have two different nomenclatures of designation depending on the assay used. In the ELISA test, which uses specific antigens, the two antibodies are proteinase three (pr3) and myeloperoxidase (MPO).  These correlate mainly (and there are some exceptions) with the immunofluorescent patterns of C and P ANCA respectively.

What about disease associations? Granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) is generally associated with C ANCA. Microscopic polyangiitis (MPA) is generally associated with P ANCA. The same is true of pauci immune  renal limited vasculitis. These categories are not absolute.

When it comes to EGPA it's a little more complex. Only 40% or so of patients with EGPA are ANCA  positive and the predominant pattern is ANCA P.  Test characteristics of ANCA for GPA,  MPA and renal limited vasculitis are pretty good. This, as is evident from the above, is not the case for EGPA.

Now on to the paper.

Despite the poor test characteristics the consensus panel recommends testing on all patients or suspected EGPA patients because it may point to the correct diagnosis and has implications for disease phenotype. Here's the specific recommendation, from the abstract of the paper:

MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms; purpura; polyneuropathy; unexplained heart, gastrointestinal, or kidney disease; and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic workup for EGPA. Patients with MPO-ANCA–associated EGPA have vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations, more frequently than patients with ANCA-negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having “vasculitic” or “eosinophilic” EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab, or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.

According to the paper there are some important clinical correlations. EGPA patients who are anca positive tend more to have a vasculitic  manifestations such as glomerulonephritis, neuropathy, pulmonary Hemorrhage and skin lesions. Those who are negative tend more toward the infiltrative aspects of the disease which translates into cardiac involvement and pulmonary granulomas.

Treatment decisions are made more on clinical grounds than on the basis of the ANCA test. Again, from the paper:

Glucocorticoids  are  the  cornerstone  of  therapy  for  EGPA.  Additional  immunosuppressive agents  (e.g.,  cyclophosphamide)  should  be  prescribed  for  patients  with  life-  and/or  organ-threatening manifestations, such as heart disease, glomerulonephritis, alveolar hemorrhage or mononeuritis  multiplex,  and  can  be  considered  for  selected  patients  with  glucocorticoid dependence  or  recurrent  disease  [51].

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.

Paget’s disease of bone

From a recent review article:

The most likely etiology is a slow paramyxoviral infection in genetically susceptible individuals; however, the exact cause is unknown. Enhanced bone resorption due to an increased activity of osteoclasts recruits numerous osteoblasts to resorption sites, with large quantities of new bone matrix produced as a result. The accelerated bone resorption and formation are not as closely coupled as in a healthy bone; a disorganized bone tissue is formed. Many patients are asymptomatic; rising serum alkaline phosphatase or incidental finding of characteristic radiographic lesions are often the only diagnostic clues. Common clinical manifestations include bone pain, bowing of long bones, enlarged skull, and hearing loss. An elevated serum alkaline phosphatase level correlates with the disease activity. The diagnosis is confirmed by characteristic radiographic findings and by nuclear scintigraphy of the bone (the most sensitive test).

Understanding premature cardiovascular disease in SLE

This was the topic of a recent review:

Purpose of review

The mechanisms leading to the development of premature atherosclerosis and vascular injury in systemic lupus erythematosus (SLE) remain to be fully elucidated. This is a comprehensive review of recent research developments related to the understanding of cardiovascular disease (CVD) in lupus.

Recent findings

SLE patients with lupus nephritis display significantly increased risk of myocardial infarction and CVD mortality than SLE patients without lupus nephritis. SLE disease-related parameters could be taken into consideration when calculating CVD risks. The type I interferon pathway is detrimental to the vasculature and may contribute to the development of insulin resistance. The level of low-density granulocytes, a distinct subset of proinflammatory neutrophils present in SLE, was independently associated with coronary plaque burden and endothelial dysfunction. Invariant natural killer T cells may promote an atheroprotective effect in SLE patients with asymptomatic atherosclerotic plaques. Oxidized lupus high-density lipoprotein promotes proinflammatory responses in macrophages.

Summary

Recent discoveries have further strengthened the critical role of SLE-related immune dysregulation and metabolic disturbances in promoting accelerated CVD. Understanding how these pathogenic factors promote vascular injury may provide better molecular candidates for therapeutic targeting, and ultimately to improve CVD outcomes.

The use of steroids and antimalarials in SLE

From a review:

Abstract:

Purpose of review

The purpose of this review is highlighting the most recent evidence on the clinical efficacy and toxicity of glucocorticoids and antimalarials in systemic lupus erythematosus (SLE) and provide recommendations on their current use.

Recent findings

Glucocorticoid toxicity is well known. Recent data confirm the increased risk of infection and damage accrual. An observational study form Hong Kong has seen increased mortality among users of high-dose prednisone regimes. Several studies support the efficacy of medium-low doses and methyl-prednisolone pulses in lupus patients, both with and without nephritis.

New data confirm the effects of antimalarials in preventing SLE activity, damage and infections, and in decreasing mortality. New screening recommendations for hydroxychloroquine maculopathy have been recently published. Combining mepacrine and hydroxychloroquine in patients with refractory cutaneous and/or articular lupus activity has proved highly effective.

Summary

Universal therapy with hydroxychloroquine should be aimed to patients with SLE without contraindications. Doses greater than 4 mg/kg/day should be avoided and regular eye screening warranted to minimize the risk of macular toxicity. Every effort should be made to reduce the dose of oral glucocorticoids. In moderate-severe flares, pulse methyl-prednisolone are more effective and much less toxic than increasing the oral doses of prednisone.

Raynaud’s phenomenon FAQs

Here are some points from a NEJM review.

What is the current classification?

Primary versus secondary.

What is the significance of one designation over the other?

Primary Raynaud’s implies that there is no underlying connective tissue disease and hence a better prognosis. Primary Raynaud’s is not associated with digital ischemia. The secondary designation implies an underlying disease association.

How are the two types differentiated clinically?

Clinical criteria (history and physical exam) and nail fold capillaroscopy are the most important means. Serologic testing has an ancillary role.

Can primary Raynaud’s progress to secondary? What are the risk factors?

From the review:

One study showed that 37.2% of 3029 persons who were thought to have primary Raynaud’s phenomenon subsequently had a connective-tissue disease.11

Whether this reflects initial misdiagnosis or actual progression is unclear.

Concerning risk factors:

Recent studies have emphasized that factors such as the onset of Raynaud’s phenomenon near the age of 40 years, severe frequent events, and the presence of abnormal nailfold capillaries (Figure 1) can help predict whether a connective-tissue disease will develop11 and are especially helpful in identifying early scleroderma.13 A survey that followed 299 patients with primary Raynaud’s phenomenon for a median of 4 years showed that if capillaroscopy reveals normal nailfold capillaries and if all tests for scleroderma-specific antibodies are negative, then the chance that scleroderma will develop is less than 2%.

What are the disease associations in secondary Raynaud’s?

The following were listed in the review.

Connective tissue diseases: systemic sclerosis, SLE, dermatomyositis, sjogrens, mixed connective tissue disease and undifferentiated CTD.

Hematologic disorders: cryoglobulinemia, cryofibrinogenemia, cold agglutinin disease and paraneoplastic syndromes.

Miscellaneous causes include hypothyroidism, peripheral vascular disease and various drugs.

Drug induced lupus

It used to be procainamide, hydralazine and INH but things have since shifted.

White board notes: Sjogren’s syndrome

Below are key points drawn from a recent NEJM review on the topic as well as E Medicine’s chapter.

Of related interest: pulmonary manifestations of rheumatic diseases [1] [2]

Testosterone replacement in men with low T

Bone mineral density and bone strength improved, but we need to find out about fracture risk.

What is Jaccoud’s arthropathy and what are the disease associations?

From a recent review:

Jaccoud's arthropathy (JA) is a condition characterised clinically by 'reversible' joint deformities such as swan neck, thumb subluxation, ulnar deviation, 'boutonniere' and hallux valgus, along with an absence of articular erosions on a plain radiograph. JA was initially described in patients with rheumatic fever (RF), but as this disorder has become rare the main clinical entity associated to JA at present is systemic lupus erythematosus (SLE). JA has also been described in other connective tissue diseases, infections and neoplasia. In general, its prevalence in either SLE or RF is around 5%. The etiopathogenic mechanisms of JA are not known, but some authors have suggested an association with hypermobility syndrome. Several studies have attempted to identify an association of different antibodies with JA in SLE patients, but their findings do not allow for the drawing of any definite conclusions. Newer imaging techniques such as magnetic resonance and high-performance ultrasonography have revealed the presence of small erosions in joints of a few patients with JA. Presently, the therapy for JA is conservative and based on the use of non-hormonal anti-inflammatory drugs, low doses of corticosteroids, methotrexate and antimalarials. The role of surgery through either the realignment of soft tissue around the joint--or more aggressive procedures such as arthrodesis, silastic implant and arthroplasty--needs to be proven.

Calcium pyrophosphate crystal deposition disease

Below are some key points from a couple of free full text reviews [1] [2].

Terminology has changed and can be confusing

The current official term is calcium pyrophosphate crystal deposition (CPPD). Pseudogout, a term which historically referred to the acute attacks of CPPD, has been replaced by “acute calcium pyrophosphate crystal arthritis.” The plain radiographic finding known as chondrocalcinosis is frequently replaced by the term “cartridge calcification.” CC is not universal in patients with attacks nor is it entirely specific for CPPD.

Crystal identification is important in diagnosis

As opposed to the needle like negatively birefringent crystals of gout, the crystals of CPPD are variable in shape, often rectangular, and if birefringent at all, only weakly positively birefringent.

There are some disease associations

From the second reference above:

Metabolic disease associations of CPPD include haemochromatosis (18), hyperparathyroidism (19, 20), hypomagnesemia (21) and hypophosphatasia (22). Other diseases such as diabetes mellitus and hypothyroidism do not associate with CPPD once adjusted for age (22, 23). Haemochromatosis is the only metabolic disease associated with CPPD that results in structural arthropathy, and this commonly affects the knees, wrists, hips, MCPJs, and ankles (18, 24).

There are some genetic determinants as well.

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.

An association between gout and aortic stenosis risk

From the green journal:

Conclusions

Aortic stenosis patients had a markedly higher prevalence of precedent gout than age-matched controls. Whether gout is a marker of, or a risk factor for, the development of aortic stenosis remains uncertain. Studies investigating the potential role of gout in the pathophysiology of aortic stenosis are warranted and could have therapeutic implications.

Even brief use of any NSAID is associated with increased risk of MI

BMJ report here.

Despite the evidence of cardiovascular risk piling up NSAID use will only increase as people look for ways to reduce opiate usage.

Adult onset Still’s disease

A case report and brief review.

Diuretics (thiazides and loops) associated with vertebral fracture risk in women

A retrospective cohort study, green journal.

Heavy cannabis use: bad for bone health

From the green journal:

The effects of cannabinoids on bone mass and bone turnover in humans are unknown.

Using a cross-sectional study design we found that heavy cannabis use is associated with low body mass index, high bone turnover, low bone density, and an increased risk of fracture.

Heavy cannabis use has a detrimental effect on bone health by a direct effect on the skeleton and an indirect effect mediated by low body mass index.

Pulmonary manifestations of connective tissue diseases

This post is drawn from a BMJ review which is one of the best I've seen on the topic. Though titled Management of interstitial lung disease associated with connective tissue disease it covers both treatment and diagnosis of the entire spectrum of pulmonary manifestations. Some key points are discussed below.

Systemic sclerosis

Interstitial lung disease (ILD) exists in most patients at some point in the course with a wide spectrum of severity. Pulmonary hypertension (PH) is common but less so. ILD tends to associate more with the diffuse form of SScl and PH with the limited form but the associations are not exclusive and both can occur at the same time. Nonspecific interstitial pnuemonitis (NSIP) is the most common histologic pattern but usual interstitial pneumonitis (UIP) is seen in 10-20%. Though steroids are commonly used as initial treatment across the spectrum of CTD associated ILD of a variety of causes, caution is in order with SScl due to the association of steroid use with an increased risk of renal crisis. Dosage limitations apply. Pleural involvement is unusual.

Rheumatoid arthritis

ILD is common with UIP in half or more. Airway and pleural disease are common. PH is unusual.

Sjogren's syndrome

ILD is less common than in many other rheumatic diseases but does sometimes occur in the form of NSIP and lymphocytic interstitial pneumonitis (LIP).

Mixed connective tissue disease

This was described in the 1970's as a distinct entity. Though there has been some controversy about whether it is a variant of, or overlap with other CTDs clarity is best served by considering it a separate disease defined by positivity to anti-U1 RNP. ILD is common and in the form if NSIP. PH is characteristic and a patient can have both PH and ILD. Airway disease occurs occasionally in the form of bronchiolitis obliterans (BO). Pleural (and pericardial) involvement are common.

Polymyositis and dermatomyositis

ILD is common though PH is not. The relationship between inflammatory myopathy, ILD, other pulmonary problems and various serologic patterns is complex. I discussed some of those relationships in an earlier post. Since that post, a syndrome of antibody to MDA-5 has emerged as an aggressive form of ILD associated with inflammatory myopathy. ILD may arise as the first manifestation of inflammatory myopathy, lacking findings of associated myositis.

Systemic lupus erythematosis

In lupus, ILD is less characteristic than a number of other pulmonary manifestations. Reports of ILD in lupus may in some cases actually represent MCTD. Pleural (and pericardial) involvement are more prominent. Also well known are presentations resembling acute pneumonitis: lupus pneumonitis, diffuse alveolar hemorrhage and infection. PH due to SLE per se is not characteristic but pulmonary vascular disease in the form of VTE may occur in patients at special risk (eg those with accompanying antiphospholipid syndrome). Finally shrinking lung syndrome (NOT to be confused with vanishing lung syndrome) is a condition of hypoinflation of poorly understood pathophysiology, unknown whether neuropathic, myopathic or both.

I have previously posted on this general topic here.

Update on the clinical and pathologic aspects of ANCA diseases

Free full text review.

Long term antibiotics after a diagnosis of Lyme disease

Here is a report of a randomized trial of long term antibiotics for patients with persistent symptoms attributed to Lyme disease. From the report:

Background

The treatment of persistent symptoms attributed to Lyme disease remains controversial. We assessed whether longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment.

Methods

In a randomized, double-blind, placebo-controlled trial conducted in Europe, we assigned patients with persistent symptoms attributed to Lyme disease — either related temporally to proven Lyme disease or accompanied by a positive IgG or IgM immunoblot assay for Borrelia burgdorferi — to receive a 12-week oral course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. All study groups received open-label intravenous ceftriaxone for 2 weeks before initiating the randomized regimen. The primary outcome measure was health-related quality of life, as assessed by the physical-component summary score of the RAND-36 Health Status Inventory (RAND SF-36) (range, 15 to 61, with higher scores indicating better quality of life), at the end of the treatment period at week 14, after the 2-week course of ceftriaxone and the 12-week course of the randomized study drug or placebo had been completed.

Results

Of the 281 patients who underwent randomization, 280 were included in the modified intention-to-treat analysis (86 patients in the doxycycline group, 96 in the clarithromycin–hydroxychloroquine group, and 98 in the placebo group). The SF-36 physical-component summary score did not differ significantly among the three study groups at the end of the treatment period, with mean scores of 35.0 (95% confidence interval [CI], 33.5 to 36.5) in the doxycycline group, 35.6 (95% CI, 34.2 to 37.1) in the clarithromycin–hydroxychloroquine group, and 34.8 (95% CI, 33.4 to 36.2) in the placebo group (P=0.69; a difference of 0.2 [95% CI, –2.4 to 2.8] in the doxycycline group vs. the placebo group and a difference of 0.9 [95% CI, –1.6 to 3.3] in the clarithromycin–hydroxychloroquine group vs. the placebo group); the score also did not differ significantly among the groups at subsequent study visits (P=0.35). In all study groups, the SF-36 physical-component summary score increased significantly from baseline to the end of the treatment period (P less than 0.001). The rates of adverse events were similar among the study groups. Four serious adverse events thought to be related to drug use occurred during the 2-week open-label ceftriaxone phase, and no serious drug-related adverse event occurred during the 12-week randomized phase.

Conclusions

In patients with persistent symptoms attributed to Lyme disease, longer-term antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment.