Mixed Connective Tissue Disease (Sharp’s disease)

Are You Confident of the Diagnosis?

Mixed connective tissue disease (MCTD) is a systemic autoimmune inflammatory disorder characterized by high titer U1-RNP antibodies, and clinical and serological overlap of systemic lupus erythematosus (SLE), systemic sclerosis (SScl), and polymyositis. Since the original description of MCTD in 1972 by Sharp et al, its existence as a discrete rheumatologic diagnosis has been rigorously debated.

Critics of the concept of MCTD as a disease entity argue that many patients initially diagnosed with MCTD later meet criteria for SLE or SSc, that autoantibodies cannot define a diagnosis, and that patients diagnosed with MCTD are not a homogeneous population with similar prognoses and response to therapeutics. Supporters of the concept of MCTD as a distinct diagnosis recognize that these same problems hold true for other autoimmune diagnoses such as SLE and Sjögren’s syndrome.

There are four published criteria for the diagnoses of MCTD. Most authors use the Alarcon-Segovia criteria because of its simplicity, and high sensitivity and specificity (90% and 98% respectively). The criteria require high titer U1-RNP antibodies (defined as greater than 1:1600 with hemagglutination), and three of five additional signs: hand edema, synovitis, myositis, Raynaud’s phenomenon, and acrosclerosis.

It has been argued that the presence of anti-Smith (Sm) or anti-double stranded DNA (dsDNA) antibodies should serve as exclusion criteria. The patient should also not meet criteria for other autoimmune disorders. As in most autoimmune diseases, the pattern of involvement may change over time, resulting in a different diagnosis. Up to 75% of patients initially diagnosed with MCTD will meet criteria for SLE or SSc with prolonged follow-up.

What you should be alert for in the history

Patients with MCTD may present to dermatology for evaluation of Raynaud’s phenomenon and swollen “puffy” hands. MCTD may also present with arthritis, arthralgias, esophageal dysmotility, interstitial lung disease (ILD), pulmonary artery hypertension (PAH), myositis, serositis, and much less commonly renal and central nervous system involvement.

Trigeminal neuralgia has been described as a rare presenting symptom of MCTD. There are also rare reports of patients with MCTD presenting with photo-distributed papulosquamous eruptions consistent with subacute cutaneous lupus erythematosus, cutaneous small vessel vasculitis, and livedoid vasculopathy.

The diagnosis of an autoimmune disease is based on groups of signs, symptoms, and serologies (Table I). To discern MCTD from SLE, polymyositis, and SSc, a full autoimmune review of symptoms should be completed.

Table I.

System	Questions	SLE	CLE	SSc	MCTD	DM
General	Do you have less energy? Has your weight changed? Are you experiencing fevers? Do you feel stiff in the morning? How long does the stiffness last?	Fatigue Weight loss Fevers 30+ min AM stiffness, hands most common	Fatigue	Fatigue Weight loss Fevers 30+ min AM stiffness, hands most common	Fatigue Weight loss Fevers 30+ min AM stiffness, hands most common	Fatigue Weight loss Fevers 30+ min AM stiffness, hands most common
Skin	Do you get rashes? Where do they occur? Do they heal with scarring? Have you noticed thickening of the skin of your hands or face? Have you noticed new blood vessels on their face or chest? Are you able to open your mouth as wide as previously?	“butterfly rash” of ACLE most specific, but can also have SCLE, CCLE, and lupus non-specific cutaneous findings such as vasculitis Nailfold capillary dilation	ACLE – butterfly rash SCLE – photodistributed erythema, or papulosquamous eruption DLE – scarring, alopecia, most common head and neck, check conchal bowls	Skin thickening of the hands, forearms, face Telangiectasias on the face and chest Decreased oral aperture Early nailfold capillary dilation, then drop out of vessels in later disease	Skin thickening of the hands Rare lesions consistent with SCLE Rare small vessel vasculitis	Heliotrope rash Gottron’s papules and signs V-neck erythema Shawl sign Mechanic’s hands Raynauds Nailfold capillary dilation
Photosensitivity	Are you sensitive to the sun? Do you form rashes with sun exposure? How soon after sun exposure do you form rashes? Do you increased fatigue, joint or muscle pain with sun exposure?	+ photosensitivity				+ photosensitivity
HEENT	Is your hair thinning? Do you get ulcers in your mouth or nose? How often do the ulcers occur? How long do the ulcers last? Do you have dry eyes? Are you able to wear contacts? Do you have dry mouth? Have you ever had eye inflammation that required steroid treatment?	Hair thinning Mucosal ulcers Secondary Sjögren’s		Hair thinning Secondary Sjögren’s	Hair thinning Secondary Sjögren’s	Hair thinning Secondary Sjögren’s
Respiratory	Are you short of breath? At rest, or with activity? If with activity, how much activity? Do you have a cough? When is the cough worse? Is it productive? Do you have pain with deep breathing?	Rare lung involvement Pleurisy		ILD PAH	ILD PAH	ILD
Cardiovascular (CV)	Do you have chest pain? Where is the pain? How long does it last? Is it accompanied with additional symptoms (shortness of breath, dyspnea on exertion nausea/vomiting, arm or face dysthesias, diaphoresis, etc)	Pleurisy
Gastrointestinal (GI)	Do you feel full early in a meal? Do you feel bloated? Are you having diarrhea? Do you have heartburn? Do you have difficulty swallowing? If so, do you have more problems with solids or liquids?			GI sclerosis GERD (reflux esophagitis)		Esophageal dysmotility
Vascular	Have you ever had a blood clot? A miscarriage? If so, at what point in the pregnancy did the miscarriage occur? Were you able to have children after the miscarriage? Do you have difficulty with cold temperatures? Are you able to reach into the refrigerator or freezer? Can you hold a cold beverage with your bare hands? Do your fingers turn red, white, and blue with cold exposure? Have you ever had ulcerations or gangrene of your fingers secondary to these changes with cold exposure? What is your normal blood pressure?	+ APLA (antiphospholipid antibodies) + Raynauds Lupus nephritis		+ severe Raynauds Digital ulcerations and pulp loss Risk of renal crisis	Raynauds	Raynauds
Musculoskeletal	Are you having joint pain? What joints bother you? What time of day is worse for your joint pain? Muscle pain? Have you noticed muscle weakness? What activities have become difficult secondary to your muscle weakness?	Non-erosive arthritis		Non-erosive arthritis	Non-erosive arthritis	Non-erosive arthritis Myositis and associated weakness
Neurological	Have you ever had a seizure or an episode of psychosis? If so, was an underlying etiology found?	Lupus cerebritis			Rare reports of preceding trigeminal neuralgia
Hematologic	Has anyone ever told you that you had low blood counts? Have you ever required a transfusion?	Cytopenias			Rare cytopenia
Renal	Do you have kidney disease? Have you been told you have protein in your urine? Have you ever been hospitalized for kidney problems?	Lupus nephritis		Renal crisis
Immunogical	Do you have risk factors for Hepatitis B or C? Do you know your hepatitis B and C status? Have you had + ANA in the past?	ANA ds DNA (more worrisome for renal disease) Sm SSA/SSB	SSA/SSB – especially in SCLE	Scl-70 (diffuse cutaneous systemic sclerosis) Centromere (limited cutaneous systemic sclerosis) ANA	ANA with high titer U1RNP	Anti-synthetase antibodies ANA

Characteristic findings on physical examination

Because MCTD is an overlap syndrome, there are no characteristic findings on physical examination. The vast majority of patients will present with a non-erosive arthritis of the joints in the hand and Raynaud’s phenomenon. Approximately two-thirds will present with hand swelling. Sclerodactyly is often seen as well. There are rare reports of patients with MCTD presenting with photodistributed papulosquamous eruptions consistent with subacute cutaneous lupus erythematosus, cutaneous small vessel vasculitis, and livedoid vasculopathy.

A comprehensive examination should be performed to evaluate for alopecia, discoid lesions, facial erythema, conjunctival injection, hypophema, a decreased oral aperture, decreased salivary pooling, oral or nasopharyngeal ulcers, facial telangiectasias, lymphadenopathy of the pre- and post-auricular, cervical, submental, submandibular, axillary and inguinal chains, parotiditis, hip and shoulder girdle weakness, thickening of the skin of the dorsal hands and forearms, photo-distributed erythema/papulosquamous eruptions, Gottron’s signs and papules, evidence of synovitis, cutaneous signs of vasculitis, and nail fold capillary changes.

Expected results of diagnostic studies

There are no characteristic histopathologic findings for MCTD. By definition, 100% of patients with MCTD will have a positive antinuclear antibody (ANA) in a speckled pattern with high titer U1-RNP autoantibodies. Approximately 30 to 100% of patients will also have a positive Rheumatoid factor. Patients with MCTD should not have positive anti-Sm, dsDNA, Scl-70, anti-centromere, or anti-Jo antibodies. Rare patients will have positive SSA and SSB antibodies..

As mentioned previously, the Alarcon-Segovia criteria can be used as a fairly accurate diagnostic tool. The criteria require high titer U1-RNP antibodies (defined as greater than 1:1600 with hemagglutination), and three of five additional signs: hand edema, synovitis, myositis, Raynaud’s phenomenon, and acrosclerosis. Patients who meet criteria for SSc or SLE are given these diagnoses instead. Presence of anti-Sm, anti-dsDNA, anti-Scl-70, and anti-centromere antibodies should steer one to reconsider the diagnosis of MCTD, as should renal or central nervous system involvement other than trigeminal neuralgia.

Who is at Risk for Developing this Disease?

MCTD is a very rare systemic autoimmune disorder with an estimated prevalence of 10/100,000 people. Women are at nine times the risk of the disease as men. In contrast to SLE, there appears to be an equal prevalence between whites and blacks. Patients with HLA-DR4 and DR1 appear to be at higher risk of MCTD.

What is the Cause of the Disease?

Etiology

The etiology of MCTD is unknown. Genetic predisposition likely plays a role, reflected in the associated increased risk with HLA subtypes DR4 and DR1.

Pathophysiology

By definition, all patients with MCTD have high titer autoantibodies to U1-RNP, an RNA particle that splices mRNA. It is postulated that these autoantibodies play a role in disease etiology, but this has yet to be confirmed. These autoantibodies are thought to form by a breakdown of self-tolerance during the clearance of apoptotic cells. These apoptotic cells form surface blebs filled with intranuclear material that is ultimately recognized as foreign.

Others have postulated that these autoantibodies are formed via molecular mimicry of common viruses, such as the Epstein-Barr Virus (EBV). Anti-U1-RNP antibodies are thought to cause vascular damage via upregulation of adhesion molecules targeting cytotoxic cells, or activation of the complement cascade Patients with MCTD also produce anti-endothelial cell antibodies and antiphospholipid antibodies that may further contribute to vascular damage.

Systemic Implications and Complications

Patients with MCTD are at high risk of interstitial lung disease (ILD) and isolated pulmonary artery hypertension (PAH) and should be screened with yearly transthoracic echocardiograms (TTE) and pulmonary function tests (PFTs) with diffusion capacity (DLCO). A low DLCO should prompt further evaluation for ILD with a high resolution CT scan. If the high resolution CT scan does not show evidence of lung fibrosis, a right heart catheterization for more careful evaluation for PAH may be warranted.

Regular monitoring for cytopenias via complete blood counts, myositis via creatinine kinase and aldolase, and proteinuria via urinalysis is also recommended.

Treatment Options

Treatment options are summarized in Table II.

Table II.

Medical Treatment	Physical Modalities
Mild Symptoms (fatigue, arthralgias, arthritis): Nonsteroidal antiinflammatory drugs (NSAIDs) Hydroxychloroquine 6.5 mg/kd/day Low-dose prednisone	Physical therapy
Raynaud’s Phenomenon Nifedpine Sildenafil	Cold avoidance/clothing layers Warming gloves

Optimal Therapeutic Approach for this Disease

Most patients with mild MCTD can be managed with NSAIDs for their arthralgias and arthritis and cold avoidance for their Raynaud’s phenomenon. Some patients report diminished fatigue and joint aches with hydroxychloroquine. Hydroxychloroquine should be dosed at 6.5mg/kd/day of ideal body weight.

Patients should be counseled of the risk of cutaneous blue-grey pigmentation, and retinopathy. Patients should have a baseline visual field exam within the first three months of hydroxycholorquine therapy, and every six months thereafter. Hydroxychloroquine is usually not effective until taken concurrently for two to 3 months. Patients with Raynaud’s phenomenon should be counseled on cold avoidance, clothing layering, and smoking cessation.

Patients with severe Raynaud’s phenomenon may benefit from calcium channel blockers such as nifedipine and felodipine, or cGMP phosphodiesterase inhibitors such as sildenafil. Nifedipine can be started at 30mg by mouth daily and slowly titrated up every 2 weeks until Raynaud’s phenomenon is improved, or side effects occur. Felodipine has a higher specificity for peripheral vasculature, and therefore is a good option as well. Felodipine can be started at 2.5mg by mouth twice daily. Sildenafil, a cGMP phosphodiesterase inhibitor, has provided patients some relief at a dose of 50mg by mouth three times a day. Patients should be counseled on the risk of hypotension with either of these classes of medications.

Patients with Raynaud’s phenomenon may also benefit from serotonin re-uptake inhibitors (SSRIs). SSRIs deplete platelet serotonin and therefore inhibit aggregation. I usually add flouxetine at a dose of 20mg by mouth daily to a vasodilating medication. Patients should be counseled on the risk of hypotension with either of these medications.

Patients who develop myositis should be treated with systemic glucocorticoids at doses of 1 mg/kg/day. Patients should be treated with corticosteroids for at least 6 weeks before being labeled steroid-resistant. Myositis often requires a very long (years) steroid taper. Corticosteroids require careful monitoring of blood pressure, blood sugar and cholesterol levels.

Patients with myositis should have a baseline bone density evaluation, such as a DEXA scan, and should be started on prophylactic calcium, vitamin D and bisphosphonates at the initiation of steroid therapy. Women of childbearing age should be counseled on the unknown side effects of bisphosphonates on the developing fetus. Steroid-resistant myositis is often treated with the addition of alternative immunosuppressants such as methotrexate or mycophenolate mofetil.

Patients who develop signs of systemic vasculitis, renal involvement, ILD, and/or PAH should be referred to the appropriate medical sub-specialties.

Patient Management

Patients with MCTD should be monitored for signs and symptoms that would qualify them for diagnoses of SLE, SSc, or polymyositis. Semiannual and symptom-directed monitoring for cytopenias via complete blood counts, myositis via creatinine kinase and aldolase, and proteinuria via urinalysis is recommended. Yearly monitoring for the formation of anti-Sm, anti-dsDNA, anti-Scl-70, and anti-centromere antibodies can also be considered.

Patients with MCTD must have a yearly TTE to assess for PAH and yearly PFTs with DLCO to assess for ILD. Development of SLE should prompt initiation of hydroxychloroquine, and counseling on ultra-violet protection. Development of myositis should prompt treatment with systemic steroids. Development of PAH or ILD should prompt referral to the appropriate medical sub-specialist.

The patient and their family should be counseled that autoimmune inflammatory diseases are diagnosed based on pattern recognition. Early in the disease process it is possible that key signs and symptoms of the ultimate diagnosis may be missing, and therefore continued monitoring must occur.

With time, additional signs and symptoms may develop that will alter the initial diagnosis. Alternatively, they may never form additional signs and symptoms. Unfortunately we do not understand enough about autoimmune inflammatory diseases at this time to predict who will improve, who will form new symptoms, and who will stay the same.

Unusual Clinical Scenarios to Consider in Patient Management

The diagnoses of MCTD is, in itself, often a clinical conundrum. Making a diagnosis of MTCD requires careful assessment of the patient’s history, review of systems, physical examination, and serologies. Exclusion of SLE, SSc, and polymyositis can be difficult. Patients must also be re-examined at regular intervals, lest new signs or symptoms emerge that change their clinical pattern and thus their diagnosis.

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