A complex case

Ankylosing Spondylitis managed with biological therapy (etanercept)--high index of suspicion in a patient presenting with a peri-orbital rash

Mr Smith is a 30 year old man who works full time in local government. His position often requires him to travel to remote communities. He presented with very mild tenderness and slight erythema in an arc under his right eye lid. The rash was not painful to touch but ached at times and his right eye felt dry. The sensation was "completely different" to his previous recurrent outbreaks of "cold sores" on his lips and nasal mucosa. There was no visual disturbance.

PMHx

• Ankylosing Spondylitis
• Psoriasis
• Recurrent HSV1 (herpes labialis/ "cold sore") outbreaks on lips and nasal mucosa

Medications

• Valcyclovir 1g BD (under care of a virologist)
• Etanercept 50mg s/c twice a week

On examination

Mr Smith looked well but anxious. He was afebrile and well hydrated.
Visual acuity was 6/5 in the right eye and 6/6 in the left.
There was no foreign body
Fluroscene staining did not show any ulceration

The skin under the right eye was a salmon pink colour and looked almost like the dry rash of psoriasis. There were no vesicles. There was very slight "puffiness" of the lower eye lid.

Initial management

I treated him with oral antibiotics for early peri-orbital cellulitis and asked him to return for review in 1 to 2 days if there was no improvement.

Follow up Mx

He returned for review and described that the area was becoming more painful but lacked the neuropathic pain and tingling associated with his usual HSV1 outbreaks.

On examination this time there was the appearance of dry raised areas/ ? early vesicles under the right eyelid. The medial aspect of the eye appeared slightly inflamed.

I took a viral swab. and contacted the opthalmology registrar who said it wasn't his field and to talk to a dermatologist!.. After some convincing he was able to say he agreed with the management plan of continuing the antibiotics and changing the antiviral to aciclovir 800mg orally 5x a day for 7 days.
A few days later he presented on the weekend and saw a colleague who was concerned about the appearance of his eye and the increasing pain. Another discussion with the reluctant ophthalmology registrar led to the initiation of aciclovir 5% cream being added.

When I phoned the patient after the weekend to advise that the viral swab had come back positive for HSV1 and to see how he was going he reported that the lesions were improving and there were no concerning eye symptoms.

Questions

1. What is the role of biologic therapies in ankylosing spondylitis?
2. What precautions must be taken with a patient on biological therapies?
3. What is the difference in presentation and pathophysiology of herpes simplex, herpes zoster and varicella zoster?
4. What is the recommended treatment for each (adults, children, pregnancy)?
5. Explain briefly the presentation, investigation ad management of ankylosing spondylitis?

Answers below come from Australian Doctor 2008 Managing Ankylosing Spondylitis, and RACGP Australian Family Physician.

What is the role of biologic therapies in ankylosing spondylitis?

There are a range of "biologic therapies" but those listed in Australia for the treatment of ankylosing spondylitis are:

1. Infliximab (Remicade. IV)
2. Adalimumab (Humira. Sub cut) 
3. Etanercept (Enbrel)

The are drugs which are directed against tumor necrosis factor (TNF) alpha. TNF alpha is a pro-inflammatory cytokine responsible for inflammation in a number of chronic disease states.

Both infliximab and adalimumab are anti TNF α monoclonal antibodies that bind specifically to human TNF α and nuetralise the biological activity of TNF-α by in stopping it binding to its receptors. They do not bind to TNF-Beta.

Etanercept works differently--it acts as a "decoy receptor" to competitively inhibit the binding of TNF to its genuine receptor. Etanercept binds to both TNF-alpha and to TNF-beta rendering them biologically inactive by inhibiting their interaction with cell surface TNF receptors.
 As a group, all of the anti-TNF therapies are effective for treating the symptoms of ankylosing spondylitis, with dramatic improvements in spinal pain, spinal stiffness, fatigue, peripheral joint inflammation, physical function and quality of life. Anti-TNF alpha therapy also reduces the occurrence of uveitis flares associated with ankylosing spondylitis

How do patients qualify for anti TNF alpha therapies?

• These medications can ONLY be prescribed by specialists
• Patients must have severe active ankylosing spondylitis with a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of at least four.
• They must fulfil the modified New York classification criteria* for ankylosing spondylitis, which includes at least grade 2 bilateral or grade 3 unilateral sacroiliitis on X-ray.
• Patients must also have documented failure of at least two NSAIDs and an appropriate exercise program for the entire three months before assessment.
• C-reactive protein and/or ESR must be elevated no more than four weeks before assessment.
• Once therapy has been established, the patient needs to show a significant improvement in both BASDAI and inflammatory markers to be able to continue on the drug. 

* Modified New York criteria for classification [9]

Definite AS if criterion 4 and any one of the other criteria are fulfilled.

1. Low back pain of at least 3 months' duration that is improved by exercise and not relieved by rest.
2. Limited lumbar spinal motion in sagittal and frontal planes.
3. Chest expansion decreased relative to normal values for sex and age.
4. Bilateral sacroiliitis grade 2 to 4, or unilateral sacroiliitis grade 3 or 4.

 

Table 2 (above) is from the RACGP AFP article Clinical use of anti-TNF-α biological agents

What precautions must be taken with a patient on biological therapies?

• Reactivation of TB has been reported so  pre-treatment screening with CXR and QuantiFERON-TB Gold assay is essential.
• The most important adverse effect is the increased risk of severe infection: patients on these medications are immunosuppressed. Be especially vigilant in patients already at increased risk of infection such as those with diabetes.
• The GP sould have a lower threshold for initiating antibiotic therapy when managing patients on anti TNF-alpha medications.
• Live attenuated vaccines must not be given.

Table 4 (above) is from the RACGP AFP article Clinical use of anti-TNF-α biological agents

What is the difference in presentation and pathophysiology of herpes simplex and varicella zoster?

            Herpes simplex virus type 1 (HSV-1)

Note most of this section uses information from Up To Date

Also called herpes labialis, is the cause of vesicular lesions "cold sores" of the mouth. HSV-1 can cause clinical disease in the genitals, liver, lung, eye, and central nervous system. These infections can be severe, particularly in the setting of immunosuppression.
Once the patient has been infected (this primary infection may not cause any symptoms) the virus lives dormant in nerve cell bodies until reactivated (by stress or another trigger factor).
The reactivation of the infection is usually preceded by pain, burning, itching and tingling. The outbreak may spread to other sites (near or far from the original infection) but recurrences are usually less severe each time.
Immunocompromised people are at risk of viral dissemination to the lungs or GI tract or CNS.

            OCULAR INFECTIONS

Primary ocular HSV infections occur in less than 5 percent of patients, but can cause significant morbidity due to keratitis and acute retinal necrosis.

            Keratitis

Recurrent HSV-1 keratitis is a leading cause of corneal blindness. HSV keratitis has an acute onset with pain, visual blurring, and discharge. Physical examination is notable for chemosis, conjunctivitis, decreased corneal sensation, and characteristic dendritic lesions of the cornea.

swollen conjunctiva (chemosis)

HSV Keratitis and dendritic ulcer

            Conjunctivitis and blepharitis

HSV-1 can present as a unilateral conjunctivitis and/or blepharitis with the development of vesicles on the lid margin. Associated symptoms include chemosis, edema of the eyelids, and tearing.

            MEDICAL TREATMENT of HSV KERATITIS

Topical glucocorticoids should not be used!!

Topical antiviral therapy has been the standard for treatment although oral antivirals are equally effective and may be more convenient.
When topical antivirals are used, a randomized trial found that concomitant treatment with oral agents does not improve the outcomes.
Improvement usually occurs within a week and no agent is better to any other.

Varicella Zoster

Primary infection is called varicella or chicken pox.
The reactivation of latent varicella is called shingles or "herpes zoster". This reactivation causes a painful, unilateral, vesicular eruption and happens mostly in adults over age 60.
Onset of varicella (ie chickenpox) during pregnancy can be a disaster for the foetus, but herpes zoster (shingles) had not been shown to cause congenital varicella.
The treatment of shingles (herpes zoster) is with standard antiviral therapy.
Aciclovir is thought to be safe during pregnancy if required.
Antiviral therapy should be initiated in all immunocompromised patients, even if they present after 72 hours.

Herpes zoster opthalmicus (shingles in the eye)

This is a serious sight-threatening condition, and is due to VZV reactivation within the trigeminal ganglion. An opthalmologist should be consulted.

Patients can develop conjunctivitis, episcleritis, keratitis, and/or iritis. Early diagnosis and treatment is critical to prevent progressive corneal involvement and potential loss of vision.

The standard approach to herpes zoster ophthalmicus is to initiate antiviral therapy (acyclovir, valacyclovir or famciclovir) to limit pain, corneal damage and anterior uveitis.
Intravenous acyclovir (10 mg/kg three times daily for seven days) is suggested in the patient whose sight is threatened or who is immunocompromised.
the Australian Therapeutic guidelines (antibiotic) suggest that the oral antibiotics can be supplemented with 3% aciclovir eye ointment 5 times a day.
 

Explain briefly the presentation, investigation and management of ankylosing spondylitis?

            Definition
Ankylosing spondylitis is a chronic, systemic, inflammatory rheumatic condition primarily affecting the spine and sacroiliac joints.
            Incidence
It affects up to 1.4% of the population and affects three times more males than females.
            Presentation
It typically presents as insidious chronic pain in the lower back and buttocks in a young man, along with morning stiffness that improves with exercise.
            Later features
These include extraspinal joint pain and enthesitis (inflammation at sites where tendons or ligaments insert into bone), increasing stiffness and altered posture, and other organ involvement: acute anterior uveitis (iritis), cardiac abnormalities, chest symptoms (apical pulmonary fibrosis), renal symptoms (analgesic abuse nephropathy, IgA nephritis and secondary amyloidosis), GI symptoms (ileal and colonic mucosal ulcers).
            Diagnosis
Clinical:
Reduced range of low back movement, increased occiput to wall distance, reduced chest expansion, sacroiliac joint tenderness and signs of other joint involvement.
Laboratory:
Positive HLA-B27, raised ESR and C-reactive protein, and normocytic normochromic anaemia.
Radiological:
Sacroiliac joint changes on plain films, sacroiliitis on CT or MRI scan, spinal changes.
Trial of therapy:
Marked response to NSAIDs.
            Differential
(Rheumatoid arthritis in different joints [not HLA-B27 positive]), reactive and psoriatic arthritis, spondyloarthropathy with inflammatory bowel disease, diffuse idiopathic skeletal hyperostosis.
            Treatment
Exercise and physiotherapy; simple analgesics; NSAIDs including aspirin; anti-TNF therapy (eg, infliximab, adulimumab and etanercept); other drugs (eg, methotrexate, sulfasalazine and glucocorticoids).

A note on anterior uveitis (Iritis)

The causes can be

1. infectious (herpes simplex; herpes zoster; Syphilis; TB)
2. autoimmune (eg ankylosing spondylitis)
3. idiopathic

Clinical presentation

1. pain
2. photophobia
3. redness (ciliary flush, in a deeper level than conjunctivitis)

Iritis

Not all red eyes are conjunctivitis!!! (although this is the most common).

Causes of red eye may be from inflammation of any area in the anterior segment and include:

1. Conjunctivitis
2. Keratitis/ episcleritis/ anterior scleritis
3. Iritis (anterior uveitis)
4. Acute angle closure glaucoma

These can be differentiated by looking at the location and colour of the inflammation, as well as considering associated symptoms.

A patient with anterior uveitis will have an inflamed iris and ciliary body. The pupil may be irregular because parts of the iris can be "stuck down" with inflammation. refer for specialist slit-lamp examination.

Here is a proforma for examination of the unilateral red eye:

Unilateral red eye  

Patient name________            Date________ 

Medical history
	Yes	No
Visual deterioration
Trauma
Discharge and type
Photophobia
Contact lens wearer
Previous eye surgery

Tick points covered in examination:

­­­__General inspection of the cornea, sclera and lids

 __Lids everted to look for sub-tarsal foreign bodies

__Examine for pre-auricular nodes

__Check the visual acuity in both eyes with glasses and/or pinhole

__Examine the pupils. Check the shape and the light reflex, look for a relative afferent papillary  

    defect (RAPD)

__Examine the cornea using fluorescein 1% drops looking for corneal ulcers/abrasions

Warning features present?

•       Contact lens wearer                                                                                       yes/ no

•       Previous eye surgery or refractive surgery                                                    yes/ no

•       Decreased vision                                                                                           yes/ no

•       Severe pain                                                                                                    yes/ no

•       Nausea and vomiting                                                                                     yes/ no

•       Cloudy or opaque cornea                                                                               yes/ no

•       Dendritic ulcer                                                                                                 yes/ no

•       Hypopyon (pus in the anterior chamber)                                                        yes/ no

•       Nonreactive pupils or RAPD                                                                           yes/ no

•       Ocular trauma                                                                                                 yes/ no

•       Persisting or worsening symptoms                                                                 yes/ no

 Sight-threatening conditions presenting with painful red eye

Condition	Clinical clues	Interim management	Urgency (ophthalmological review)
corneal foreign body	history (especially high velocity) pain on lid movements photophobia visual acuity impaired	check for indication of penetrating injury immobilise head remove visible foreign body under slit-lamp examination and topical anaesthesia antibiotic drops and cycloplegic if required for pain review next day unless symptoms completely resolved	refer if suspicion of penetrating eye injury, inadequate removal, especially rust-ring, or if symptoms persist more than 2 to 3 days despite apparently full removal
bacterial infectious keratitis (inflammation of the cornea)	risk factors: contact lens wear or corneal trauma mucopurulent discharge foreign body sensation photophobia white spots on cornea spots stain with fluorescein	swab for culture (but debridement required for adequate specimen) commence antibiotics in consultation with ophthalmologist withhold antibiotics if same-day ophthalmological review possible, as may mask culture results from later debridement	same day—emergent (implies potential to change or worsen rapidly)
viral     infectious keratitis (inflammation of  the cornea)	dendritic ulcer seen with fluorescein stain foreign body sensation photophobia watery discharge	commence topical antivirals see Herpes simplex keratitis or Ophthalmic herpes zoster	within 1 to 2 days
scleritis	severe boring pain, often waking patient from sleep may have history of inflammatory rheumatological disease sclera thickened, bluish-red discoloration globe tender to palpation	an oral NSAID, see Table 1.2 consultation with ophthalmologist	within 1 day
iritis (anterior uveitis)	photophobia and pain constricted pupil injection of radial vessels around limbus cells and flare in the anterior chamber adhesions of pupil to lens hypopyon, fibrin in chamber	pupillary dilatation and cycloplegia, see Table 14.25 commence topical prednisolone if advised by ophthalmologist	same day
hyphaema	blood 'level' in anterior chamber usually history of trauma: if not, consider non-accidental injury in child or blood dyscrasia	discuss with ophthalmologist rest, eye shield avoid aspirin, NSAIDs	same day (if advised by ophthalmologist)
hypopyon	visible pus or white blood cell 'level' in anterior chamber	dilate pupil and cycloplegia, see Table 14.25 obtain blood cultures if sepsis likely check for systemic factors related to sepsis (cause or complication)	same day—emergent
acute angle-closure glaucoma	severe eye pain and tenderness to palpation haloes around lights and reduced vision eye feels hard to palpation compared to contralateral eye severe vomiting and headache photophobia fixed, irregular mid-dilated pupil	immediate referral systemic analgesics and antiemetics commence treatment in consultation with ophthalmologist while awaiting transfer (see Acute angle-closure glaucoma)	same day—emergent