Clinical Overview of Lupus/CTD(Connective Tissue Diseases)

Rich Callahan MSPA, PA-C

Fletcher Allen Health Care

Dept. of Dermatology

Burlington, VT

CTD formerly known as CVD

• Formerly known as “collagen vascular diseases,” now used interchangeably with CTD.

• The term “vascular” was included because it was recognized early on that the vascular system has a higher sensitivity to the autoimmune process that drives these diseases.

• Vasculitis, or inflammation of the blood vessels, plays a role in many of the CTD’s. This is why dilated periungual capillary loops are commonly visible in patients with Lupus, Scleroderma and dermatomyositis.

What are connective tissue diseases? (CTD)

• A group of diseases of unknown etiology affecting multiple systems within the body.

• All share a common characteristic: The presence of antibodies in the serum of ill patients.

• These autoantibodies are more than likely responsible for the diseases, although they can be elusive at times, making CTD a clinical, rather than laboratory diagnosis.

Diagnosis of CTD is tricky

• Almost always difficult to diagnose because CTD has no specific onset, duration or set of clinical characteristics.

• There are no “gold standard” tests for the diagnosis of CTD.

• For this reason, diagnosis is based on sets of clinical criteria, rather than any one diagnostic procedure.

CTD’s – Some Examples

• Lupus Erythematosus

• Dermatomyositis• Scleroderma• Relapsing

Polychondritis• Reiter’s Disease• Ankylosing

Spondylitis

• Polyarteritis nodosa• Kawasaki’s disease• Psoriatic arthropathy• Polymyositis• Polymyalgia

rheumatica• Temporal arteritis• Sjogren’s Disease

We will focus on the “big three” which will most likely be seen in

clinical practice: Lupus, Dermatomyositis and

Scleroderma.

Of the Big 3, we will focus on Lupus as it has the most dermatologic manifestations.

• What is Lupus?• An autoimmune disease of unknown origin in

which autoantibodies attract to specific types of connective tissue and cause damage resulting in clinical signs, symptoms and abnormalities.

• It’s important in dermatology because 85% of all Lupus cases have skin involvement.

• It’s not rare, and it’s not common either: About 40 cases/100,000 in North America

Why is diagnosing Lupus important?

• Because a subtype of Lupus known as SLE (systemic lupus erythematosus) can have serious multisystem involvement resulting in significant morbidity/mortality if not recognized/treated.

• Affects multiple systems within the body including immune, hematologic, neurologic, renal, cardiovascular, rhematologic and dermatologic.

• Patients who present with skin lesions suggestive/diagnostic for Lupus need a full work-up to exclude SLE.

Lupus Subtypes

• SLE: Systemic Lupus Erythematosus - Presents with a wide range of skin lesions and always has some level of multisystem involvement.

• CCLE: Chronic Cutaneous LE (or discoid lupus) - Defined by its characteristic “discoid” skin lesion. Has the least potential for systemic involvement.

• SCLE: Subacute Cutaneous LE – Also has wide range of skin lesions. Often some systemic involvement, but usually has a benign course.

• (These are the 3 common subtypes – the two others, Neonatal LE and drug-induced LE – are quite rare.)

Clinical Presentation - SLE

• Rash occurs in 85% of patients with SLE: Erythematous patches and plaques primarily on sun exposed surfaces of head, trunk and upper extremities:

• Face• Upper chest• Shoulders/extensor arms• Dorsal hands/fingers (spares the knuckles)• Lesions may/may not be scaly and never itch.• Butterfly rash occurs in 30-60% of patients with SLE• Photosensitivity in 50% of patients. Tends to be females>males,

age usually 30-40 years. More common in African-Americans

Butterfly Rash

• Also known as bi-malar rash. Often a butterfly-shaped, erythematous patch covering malar (cheek) and nasal areas. Spares nasolabial folds.

• Often triggered by recent sun exposure.

• Presents in many different ways:

– Scale/No scale

– Vesicular

– Atrophy/No atrophy– Just erythema w/o textural changes.

Additional skin lesions/signs of SLE

• Arthritis• Nephropathy• Fever• Neurologic involvement• Raynaud’s • Serositis• Thrombocytopenia• Oral Ulcers (shallow

erosions on buccal mucosa, hard palate, lips)

• Thrombosis

• Discoid/SCLE lesions (more on this later)

• Myositis

• Hemolytic anemia

Diagnosis of SLE

• Here’s where it gets tricky – no one diagnostic criteria or clinical characteristic will define the disease.

• It’s more of a clinical “big picture” diagnosis, where a group of clinical signs/symptoms/diagnostic test results meet the criteria for SLE.

• Let’s not forget, these patients are usually sick. They will complain of many other symptoms in addition to skin lesions: Joint pain, fever, lymphadenopathy, psychosis, bruising, etc.)

American College of Rheumatology: 1997 Revised Criteria for Classification of SLE.

(Presence of 4 or more compatible with SLE)

• Butterfly Rash• Discoid Rash• Photosensitivity• Oral ulcers• Arthritis• Serositis (Pleuritis or

pericarditis)• Renal disorder

(Proteinuria or cellular casts.)

• Neurologic disorder (seizures/psychosis)

• Hematologic disorder (deficiencies of all cell types)

• Immunologic disorder (presence of autoantibodies in serum)

• Positive ANA

Anti-Nuclear Antibody (ANA) is important diagnostic test for Lupus and CTD’s

• The only serum antibody test we will discuss in detail as it is common to all CTD and is the first test ordered when you suspect it.

• It is sensitive for CTD, but not specific: 95% of patients with CTD will have a positive ANA, but there are many other diseases which will have it as well.

• It is worth noting that approximately 5% of otherwise normal blood donors will have positive ANA.

Role of ANA titer in diagnosis of Lupus

• Other causes of positive ANA include neoplasms, liver disease, active chronic infections and use of birth control pills.

• A positive ANA alone will not diagnose Lupus, but will be strongly suggestive of the diagnosis if other criteria exist.

• A negative ANA strongly suggests against the diagnosis of Lupus, but does not rule it out if several other signs/symptoms of Lupus are present

ANA

• A test that detects presence of antinuclear antibodies (ANA’s) in human serum. ANA’s are antibodies that target human DNA as antigen.

• It is a direct immunoflorescence (DIF) test in which patient’s serum is placed on a substrate of cultured human cells.

• If ANA’s are present, they attach to nuclear components in the cells.

• Fluorescein-stained anti-human immunoglobulins are then applied which attach to the ANA’s.

ANA

• The prepared specimen is then viewed under fluorescent microscopy, and different patterns of fluorescence will emerge: Homogenous, speckled, peripheral and nucleolar.

• Sometimes the pattern seen will help suggest towards a certain diagnosis, sometimes not.

• The important lesson to learn is that a positive ANA accompanied by other signs of Lupus is strongly suggestive of the diagnosis needs further work-up to assess for presence of internal disease.

• The PCP at this stage would refer to rheumatology or dermatology for further evaluation if possible.

It Gets a lot more complicated!Further Lupus Evaluation

• Skin biopsy (shave>punch) of lesional skin for histopathology and perilesional skin for DIF (need to have special DIF bottle on hand.)

• Complete review of systems

• Additional antibody testing: nDNA, Ro, La, Sm, nRNP

• Urinalysis

• CBC, ESR, C3, C4

• Unless your supervising doc really knows Lupus, best to have rheumatology or dermatology pursue additional work-up.

Clinical Example

• Nicole was a 28 y/o Caucasian female patient currently under treatment for acne when she developed an asymptomatic “photosensitive” eruption on bilateral forearms.

• Although described as initially being pink and somewhat scaly by the patient, by the time I saw it a week later in had changed to a faint rash of small, slightly scaly purple papules.

• At the same time she described a recent bout of fatigue, “fevers,” headaches and loss of appetite.

It is worth noting at this point that she had an unexplained esophageal stricture about 6 months

prior

• I was treating her for acne at the time. ENT treated her with prednisone, which seemed to help, and eventually performed a procedure to relieve her esophageal stricture.

• Her symptoms stopped after the procedure.• Because her condition improved, ENT did not

look any further, and called the esophageal stricture idiopathic.

• At the time of first presentation, I didn’t link this episode to her skin rash.

First presentation of rash – a diagnostic procedure was performed

• A 4mm punch biopsy was done centered on one of the papules on her forearm, and sent for routine histopathology.

• Specimen was read as prurigo nodularis, an eczematous condition of thickened, lichenified skin from chronic rubbing and scratching.

• This biopsy resulted suggested against a diagnosis of LE

What made everything more interesting was that she was convinced the whole time that she had Lupus

• Claimed to have a strong family history of Lupus, and said this was “exactly what happened” to her aunt who had it.

• (Text books cite an incidence of positive family history in about 5% of cases.)

• Continued to complain of “fevers,” fatigue and loss of appetite. No objective signs of fever in our office.

• I had a negative biopsy, but we ordered a battery of tests anyway including a slew of antibodies, urinalysis, CBC, ESR, etc.

Clinical Example con’t

• Everything came back negative except for the ANA, which was quite elevated at a titer of 1:160, with speckled and peripheral patterns. She was on BCP’s at the time, which can falsely elevate ANA, but not usually this high.

• She came back a week later with a new photosensitive rash on her upper chest. It was blotchy, pink, poorly-defined and faint. It was not in the slightest bit scaly, and wasn’t too impressive to look at.

• She seemed more anxious and now had bilateral cervical lymphadenopathy and well as sweats and continuing fatigue.

Rheumatology to the rescue

• Although we still couldn’t prove a diagnosis or the presence of internal involvement related to Lupus, it was still strongly suspected.

• In addition, the patient seemed sick and was convinced she had Lupus.

• She was referred to rheumatology, who promptly diagnosed her with Lupus on clinical grounds and initiated treatment with Plaquenil.

• I called the patient a week later, who seemed to be feeling much better after a week of treatment.

“Plaquenil Deficiency”

• An old joke in dermatology circles.• Reserved for a small, but real group of patients in

whom LE is suspected, but can’t be proven definitively with diagnostic testing.

• When you treat them empirically with an LE drug (like plaquenil) and they get better on it, they have been diagnosed with plaquenil deficiency!

The Moral of the Story?

• SLE can be a tricky diagnosis at times, in that it can be present despite multiple negative diagnostic tests.

• It is ultimately a clinical diagnosis, which means that a practitioner who hasn’t seen it much before could be in for a hard time.

• If the suspicion for SLE is there, but you can’t prove it, refer to someone who has more experience with it.

• Always listen to the patient, because sometimes they will tell you what’s wrong with them.

• When in doubt, refer to rheumatology. Better to let them rule out LE than miss a patient who could progress to systemic involvement.

Treatment of SLE

• Oral Steroids - prednisone, prednisolone, etc. These drugs are effective anti-inflammatory treatment for various forms of internal organ involvement.

• Antimalarials – hydroxychloroquine (Plaquenil) Effective treatment for all skin lesions of LE. Generally safe for long-term treatment.

• Dapsone – a seldom-used antibiotic which shows some efficacy in treating skin lesions of LE.

CCLE – Clinical Presentation(Chronic Cutaneous LE, sometime referred to

as Discoid LE or DLE)• Classic lesion is “discoid,” or circular in shape. Usually

presents as asymmetrically scattered, raised, violaceous-to-red flat-topped plaques of 1-3cm diameter. Firmly adherent scale which has a “carpet tack” texture on its underside. (Because scaling penetrates the hair follicles.)

• Usually appear on face, scalp and neck

• Females>Males.

• Incidence peak around age 40

• UV exposure and physical trauma can induce or worsen lesions.

CCLE Lesions

• Epidermal/dermal atrophy over time leads to smooth, whitish plaques, which are essentially hypopigmented.

• This hypopigmentation is permanent and present a greater problem for darker-skinned patients.

• Chronic lesions in the scalp can be scarring, which obliterates follicular structures and ultimately results in permanent alopecia.

• Lesions can last from months to years.

Clinical Presentation of SCLE(Subacute Cutaneous LE)

• Lesions present in 2 distinct morphologic groupings

• Papulosquamous pattern SCLE: Faded to brightly erythematous scaling papules and large plaques.

• Annular-polycyclic pattern SCLE: Eruption of annular plaques, brightly erythematous with clearly-defined, raised scaly border. Lesions often have central clearing.

• In both cases, lesions spare lateral trunk, axillae, inner arms and knuckles.

• Lesions resolve with hypopigmentation and telangiectasia formation.

Other symptoms of SCLE

• Arthritis• Arthralgias• Renal disease• Serositis• CNS symptoms• Never as severe as in

SLE

• Photosensitivity• Periungual

telangiectasias• Vasculitis

Diagnosis of CCLE/SCLE

• As any patient with LE can progress to SLE, a full work-up is mandatory at baseline, even in patients who only present with skin lesions:

• H & P• Lesional biopsy for

histopathology. Perilesional biopsy for DIF.

• CBC, ESR, platelets

• ANA

• Other antibodies: nDNA, anti-RNP, Ro, La, Sm

• Urinalysis

• BUN/Creatinine

Treatment of CCLE/SCLE

• First line of defense is photoprotection, as Lupus is by nature a photosensitive disease.

• Avoid direct sun exposure between 10am-3pm.• Use broad-spectrum sunscreens (SPF 30 or higher;

zinc oxide or titanium dioxide.)• Sun-protective hats and clothing will help.

Treatment of CCLE/SCLE

• Topical Steroids (Classes I-V)

• Intralesional steroids - mostly triamcinolone acetonide (Kenalog)

• Oral antimalarials – hydroxycholoquine (Plaquenil)

• Dapsone

• Others that have been tried with varying degrees of success include: Azathioprine (Imuran,) methotrexate, thalidomide, acitretin and isotretinoin.

Treatment of CCLE/SCLE

• Primarily cutaneous, sub-acute LE can progress to SLE with multisystem involvement without warning, at any time.

• CCLE/SCLE patients need to be followed periodically with laboratory testing/office visits to monitor for this potential development of SLE.

Dermatomyositis (DM)

• An autoimmune inflammatory disease of the muscles often diagnosed by characteristic skin findings. When skin findings absent, is called polymyositis.

• Can occur in children, but more often in adults over 40. Often associated with underlying malignancy in adults.

• Proximal muscle weakness is most common presenting symptom.

• Male = female. All age groups. Approximately 5-10 cases/million adults.

Clinical Presentation of DM – Has 6 Classic Characteristics

• Heliotrope rash – violaceous hue that surrounds eyes, accompanied by periorbital and facial edema. Can also affect face, shoulders, chest. Can look/feel “like a sunburn.”

• Gottron’s papules – eruption of fixed, firm, red-to-violaceous flat-topped papules on backs/sides of fingers, may or may not spare knuckles.

Clinical Presentation of DM

• Violaceous Scaling Patches – Erythema with a purple hue distributed symmetrically in patches over knees, elbows and backs of hands. Unlike the hand rash of SLE, the knuckles are not spared.

• Periungual telangiectasias – proximal nails folds are thickened, rough and erythematous. Numerous superficial telangiectasias are visible with opthalmoscope on red 3 or with a dermatoscope.

Clinical Presentation of DM

• Symmetrical proximal muscle weakness - Usually precedes dermatologic manifestations of DM so need to assess by Get-up-and-go-test.

• If you haven’t heard of it, you will during your geriatric practicum in the winter.

• Test administered to older patients to assess muscle strength: Patient is seated upright in a chair with armrests and asked to push off the armrests and lift themselves into a standing position.

• The patient is timed and assessed for difficulty in performing the task.

Clinical Presentation of DM

• Get-up-and-go-test is a good assessment for proximal muscle weakness, and must be given to all patients presenting with skin findings suggestive of dermatomyositis.

• Weakness tends to symmetrically affect legs>arms. Slowly develops over weeks to months.

• DTR’s remain normal.

Diagnosis of DM

• Skin biopsy for histopathology and DIF

• Biopsy of weak muscles

• Muscle enzymes – CK, AST, ALT, LDH

• 24 hour urine for creatinine an even more sensitive measure of muscle damage.

• ANA

• Serum antibodies – Ro, La, Sm, nRNP, Jo-1

• Significant association with occult malignancy in adults presenting w/DM.

• Do pelvic, breast exams and mammogram. CXR, DRE, colonoscopy, PE

Treatment of DM

• DM can occur in an acute setting, or be chronic/recurrent over periods of years. Early diagnosis and treatment greatly improves patient outcomes.

• Oral steroids – first line treatment and often used chronically over long periods of time in tapering doses until remission or adequate control. (usually prednisone.) Dose can be adjusted based on improvement as indicated by periodic checks of patient’s serum CK.

• Methotrexate, azathioprine, cyclophosphamide – all potent immunosuppressants with many potential side effects.

Scleroderma(Sometimes referred to as Systemic Sclerosis)

• A rare autoimmune disease which is highly disfiguring and potentially fatal.

• Affects women 3 x > men

• Characterized by sclerotic, vascular and inflammatory changes to various tissues including skin and internal organs, often with multi-system involvement.

• Often affects lungs, heart and GI tract.

• Usual onset ages 30-50 years.

• Etiology is unknown.

Scleroderma Clinical Presentation

• Presentation often preceded by history of Raynaud’s phenomenon, migrating arthritis, dysphagia and heartburn. Also GI symptoms such as diarrhea and constipation.

• Skin disease runs characteristic course of edema to sclerosis to atrophy in affected areas of skin.

• Hands usually start with Raynaud’s (for months to years) then progress to edema, then sclerosis with ulcerations at fingertips and sclerodactyly(hard fingers). Skin becomes tight and leathery with obliteration of sweat glands and hair.

• Often seen in CREST presentation (more later)

Scleroderma Clinical Presentation

• Unusual disease in that patient’s can look much younger than actual age.

• Facial skin becomes shiny and extremely taut. Lips are thinned and nose starts to look like a beak. Many prominent telangiectasias.

• In other areas (trunk/proximal extremities) skin becomes hardened and waxy, no longer able to wrinkle or fold.

• Calcinosis Cutis – Hard, white nodules around fingertips and knuckles as a result of cutaneous calcification.

Joe Monroe (SDPA founder) uses the word CREST as a way to remember clinical criteria for

Scleroderma

• Calcinosis: especially in fingers• Raynaud’s: present in >90% of scleroderma cases• Esophageal dysmotility: leading to reflux• Sclerodactyly: hardening of skin, tapering of

distal digits• Telangiectasias: on face, chest, mouth, even

internally.

Scleroderma Clinical Presentation

• Signs of internal involvement can include:• GI: Dysphagia, constipation, diarrhea, bloating,

malabsorption.• Respiratory: Pulmonary fibrosis.• Cardiac: Conduction defects, HF, pericarditis.• Renal: Uremia, malignant hypertension.

(Leading cause of death.)• Musculoskeletal: CTS, weakness.

Diagnosis of Scleroderma

• Usually a straightforward clinical diagnosis with characteristic findings.

• Punch biopsy of lesional skin usually diagnostic.

• Do ROS with goal of finding internal involvement if present.

• PE of periungual regions with opthalmoscope on red 3 or with dermatoscope (dermlite)

• ANA

• Other antibodies: Ro, La, Sm, nRNP, Scl-70

Treatment of Scleroderma

• Treating scleroderma with internal involvement is still difficult and only partially effective. Numerous agents have been tried: Penicillamine, methotrexate, prednisone, relaxin, interferons and cyclosporine.

• Cutaneous disease is managed primarily by watching for signs of secondary infection, which can opportunize on compromised skin barrier (usual culprit is staph.)

• PT becomes important in advanced disease to maintain ROM over joints.