CHAPTER 36
Connective Tissue Disorders
Stuart A. Green, MD, FACP
The connective tissue diseases, also called collagen vascular diseases (CV), are a group of multisystem diseases. They include, but are not limited to, systemic lupus erythematosus (SLE), Sjøgren’s syndrome (SS), systemic sclerosis (SSc), rheumatoid arthritis (RA), Raynaud’s phenomenon, and the vasculitides. These are autoimmune diseases characterized by pathologic changes in the blood vessels and connective tissues. The basic cause of the defective immunity is uncertain but most likely involves an interaction between an immune system made susceptible either from genetic or epigenetic risks and environmental factors and/or pathogenic agents.
Diagnosing these diseases definitively can be difficult because diagnosis is often made by fulfilling specific criteria and not by a single lab test. The American College of Rheumatology has developed criteria for many of the CV diseases. The diagnosis is made by a combination of a comprehensive history, examination, and laboratory profile. In some cases, these diseases may overlap, adding further complexity to accurate diagnosis. However, in many of the connective tissue disorders, the combination of affected target organs may offer a clue as to diagnosis, such as in SSc, where it may be the combination of skin findings and Raynaud’s phenomenon; or in SLE, where it may be constitutional features, arthralgias, and hair loss. Many of the CV diseases have musculoskeletal involvement as an important and common feature.
The treatment of the connective tissue diseases relies on a combination of corticosteroids and other immunosuppressive medications. Through knowledge of the common and the unique clinical features, immunologic mechanisms, organ involvement, and the response to treatment, providers can have a better understanding of the connective tissue diseases.
The provider–patient relationship is essential with any disease. Given the multisystem nature of the connective tissue disorders, almost any organ may be affected. Providers need to treat the disease, but they must also understand the impact of the disease on the patient and the family as a whole. Patients need to be educated about sequelae and prognosis. Depending on the severity of the disease, connective tissue disorders affect every aspect of life, including planning and raising a family, employment, and even ability to perform the activities of daily living. Ongoing counseling must occur, and is often the role of the primary provider. National organizations such as the Lupus Foundation of America may be able to provide patient-centered information along with contacts for local support groups.
SYSTEMIC LUPUS ERYTHEMATOSUS
SLE is the second most common of the connective tissue diseases. It is a multisystem disease with a wide variety of clinical manifestations, ranging from a benign, easily treated disease with a rash and arthritis to a life-threatening illness with progressive nephritis or central nervous system damage. Like many CV diseases, SLE is characterized by exacerbations and remissions.
Anatomy, Physiology, and Pathology
SLE is characterized by excessive autoantibody production, immune complex formation, and immunologically mediated tissue injury. The pathologic findings of SLE occur throughout the body and are manifested by inflammation and blood vessel abnormalities.
SLE presents with various histologic findings, some of which are pathognomonic, whereas others are not at all specific. The pathology of the kidney has been studied extensively because renal lesions are very common and one of the major causes of morbidity. Up to 60% of people with SLE are diagnosed with lupus nephritis, which can lead to significant illness and even death (Lee, Woo, Choi, Ji, & Song, 2010). The kidney in SLE displays varying degrees of inflammation, either segmental or global, increased mesangial cells and matrix, cellular proliferation, basement membrane abnormalities, and immune complex deposition. Skin lesions in SLE show inflammation and degeneration at the dermal–epidermal junction; the complement components and immunoglobulins (IgMs) at this junction can be demonstrated in a band-like pattern by immunofluorescence microscopy, which is the basis for the lupus band test. Concentric periarterial fibrosis or onion-skin changes in the spleen are considered pathognomonic for SLE (Rao & Bowman, 2013).
Epidemiology
The prevalence of SLE varies throughout the world. Its prevalence in the United States has been estimated in the range of 15 to 50 per 100,000. It is more prevalent in women (female/male ratio of 9:1), particularly those in their reproductive years. The disease may affect as many as 1 in 1,000 young women. Initial presentation is usually between the first and fourth decade. Approximately 10% of SLE patients present after the age of 60 years. The prognosis for men and children with SLE is less favorable than for women. SLE that begins after the age of 60 years (in both sexes) tends to have a more benign course.
In the United States, SLE is more common among African Americans and Hispanics than Whites. The average incidence in the United States is 25.5 per 1 million population for White females and 75.4 per 1 million for African American females. In the United States, survival rates of 95% at 5 years are obtainable. Patients with SLE have a bimodal mortality curve. Those dying within the first 5 years typically die from either their lupus or consequent infections. Those dying later are more prone to cardiovascular events (Urowitz & Gladman, 2000).
African American patients with SLE have also been shown to have anti-Smith (antiSm) antibody and antiribonucleoprotein (antiRNP) antibody, discoid skin lesions, renal disease, and serositis more commonly (Ward, 2004) and are considered to have a poorer prognosis than White patients. White patients with <12th-grade education, and consequently a lower socioeconomic status, do not do as well as those with higher levels of education. Lower socioeconomic status in African Americans is associated with greater all-cause mortality; however, under-assignment of mortality due to SLE has hampered accurate conclusions about the impact in this group of patients (Ward, 2004).
Diagnostic Criteria
In 2012, the Systemic Lupus International Collaborating Clinic (SLICC) group published a revised criteria list that improved diagnostic sensitivity (Petri et al., 2012). This list was divided into clinical and immunologic parameters and a patient would be classified with SLE if four criteria were present with at least one clinical and one immunologic parameter. A patient can also be classified as having SLE if there was a renal biopsy compatible with lupus nephritis and either a positive antinuclear antibody (ANA) or dsDNA was present (Table 36.1).
History and Physical Examination
The most important part of the examination of the patient suspected of having SLE is the history. The patient must be asked about systemic symptoms such as fever, malaise, and weight loss; musculoskeletal complaints such as arthritis and arthralgia, myalgias; cardiopulmonary complaints such as chest pain and shortness of breath; cutaneous lesions including alopecia, rash, photosensitivity, and oral or nasal ulcers; and nervous system complaints such as headaches and migraines, psychosis, depression, and seizures. In essence, the criteria list should be used as a framework to conduct the history. The family history is very important because 10% to 15% of patients have a first-degree relative with SLE and 18% to 22% of patients have a relative with SLE (Rao & Bowman, 2013).
SLICC Classification Criteria for SLE 2012 |
CLINICAL CRITERIA |
1. Acute cutaneous lupus 2. Chronic cutaneous lupus 3. Oral or nasal ulcers 4. Nonscarring alopecia 5. Synovitis (arthritis) 6. Serositis (pleural/pericardial pain) 7. Renal—urine protein-to-creatinine ratio or red blood cell casts 8. Neurologic (seizures/psychosis) 9. Hemolytic anemia 10. Leukopenia (4,000/mm3 at least once) or lymphopenia (<1,000/mm3 at least once) 11. Thrombocytopenia (<100,000/mm3) at least once |
IMMUNOLOGIC CRITERIA |
1. ANA level above laboratory reference range 2. Anti-dsDNA antibody level above laboratory reference range. 3. Anti-Sm: presence of antibody to Sm nuclear antigen 4. Antiphospholipid antibody positivity. 5. Low complement (low C3, low C4, low CH50) 6. Direct Coombs’s test in the absence of hemolytic anemia. |
Note: Criteria are cumulative and need not be present concurrently. |
ANA, antinuclear antibody; anti-dsDNA, anti-double-stranded DNA; SLE, systemic lupus erythematosus; SLICC, Systemic Lupus International Collaborating Clinic.
Source: Adapted from Petri et al., 2012.
The examination of the patient should not be limited to the skin or the musculoskeletal system; attention should also be paid to other organ systems for possible involvement. The examination should begin with vital signs, including temperature, respirations, pulse, blood pressure, and weight. Weight loss is often noted through serial evaluations. The skin (including mucosal surfaces), hair, and scalp are usually examined first and a thorough pulmonary, cardiac, and neurological examination is required.
Musculoskeletal features: Arthralgia or arthritis is a presenting manifestation of 95% of patients with SLE. The acute arthritis may involve any joint, but typically involves the small joints of the hands, wrists, and knees. It is characteristically episodic, oligoarticular, and migratory; unlike RA, it is rarely destructive. Joint line tenderness, at a minimum of 2 joints and 30 minutes of morning stiffness, is sufficient to fulfill the arthritis criteria in the new SLICC criteria (Table 36.1). Myalgia and generalized muscle tenderness occur frequently during exacerbations of the disease and are observed in up to 80% of patients. Tendinitis is also common and can result in tendon rupture.
Cutaneous manifestations: Skin lesions can be divided into acute and chronic lesions. The classic “butterfly” malar rash over the cheeks and the bridge of the nose is an acute lesion. It is present for days to weeks and is nonblanching and often pruritic or painful. Commonly precipitated by sunlight exposure, it occurs in only one third of SLE patients. A patchy rash on the upper trunk and sun-exposed areas (photosensitivity) is more common. Subcutaneous lupus erythematosus refers to a cutaneous lesion that is nonscarring, papulosquamous, or annular (or both), and has LE-specific histopathology. It is present on the trunk, limbs, face, and palms. Most patients with this type of rash have antibodies to the Ro (SS-A) antigen. Discoid lesions are chronic lesions characterized by follicular plugging, atrophy, scaling, telangectasias, and erythema. Some patients simply have discoid lupus and may not have evidence of systemic lupus and are typically ANA negative.
Renal disease: Clinically, renal disease is reported in about 50% of patients during the first year of the clinical diagnosis of SLE. Although most patients have some renal lesions, severe renal disease that leads to death or the need for renal transplant occurs in only a small percentage (15%–20%) of patients. A renal biopsy provides the most reliable information about the severity of renal involvement. In general, the more severe the glomerular inflammation, the worse the prognosis (Markowitz & D’Agati, 2007; Weening et al., 2004).
Neuropsychiatric manifestations (NPSLE): Neurologic manifestations of SLE are present in many SLE patients at some point during the course of their disease and can affect both the central and peripheral nervous system. Symptoms may include seizures, strokes, frank psychosis, cognitive dysfunction, aseptic meningitis, polyneuropathy, and (in 1%) peripheral sensorimotor neuropathy. Cognitive impairment may be seen in up to 20% to 30% of lupus patients. Tension and migraines may be present but are not necessarily more frequent than in the general population. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a frequent cause of aseptic meningitis in lupus patients.
Cardiopulmonary manifestations: Although pericarditis is clinically present in up to 25% of patients, pericardial lesions are found in 60% to 80% of the cases at autopsy. Pericardial effusions rarely lead to tamponade. The physical examination may reveal a pericardial friction rub, and an electrocardiogram may reveal ST elevations in the precordial leads. Pleuritic pain is a common occurrence in up to 60% of patients but is not necessarily associated with a pleural effusion. Pleural effusions generally are bilateral and may be seen in almost 50% of patients. Interstitial lung disease is infrequent and usually mild. However, lupus pneumonitis, although rare, can be catastrophic, occurring with active extrapulmonary lupus and high dsDNA titers.
Diagnostic Studies
ANA is a general term used to describe any autoantibodies directed against a component of the nucleus; they are present in many diseases. The detection of an ANA is a sensitive but not very specific screening test for SLE. ANAs occur in 95% of SLE patients. The degree of positivity of the ANAs is diagnostically important but not predictive of disease activity.
The principal tests used to follow lupus nephritis are blood urea nitrogen, creatinine, spot protein/creatinine ratio, or a 24-hour urine for protein, urinary sediment, C3, C4, and anti-dsDNA antibody. Nearly all patients with clinically important renal disease have microscopic urine findings. The finding of cellular casts, especially red cell casts, is indicative of active nephritis.
Treatment Options, Expected Outcomes, and Comprehensive Management
SELF-CARE MANAGEMENT
Although it is impossible to prevent the onset of SLE, prevention of exacerbations may be possible. Avoidance of exacerbating factors may help reduce the number and severity of flare-ups; these factors include sun exposure, injuries, insufficient rest, emotional crises, and medication cessation. Abruptly stopping medications, particularly large doses of corticosteroids, may even be fatal. Patients must be counseled about these factors. Several authors have implicated stress as a factor that can induce or exacerbate SLE. Different stress reduction techniques, such as biofeedback, visual imagery, and acupuncture, could be considered.
General therapeutic considerations must always include rest and exercise. Rest is important in the treatment of fatigue secondary to SLE both in active periods and during remissions. Exercises that strengthen muscles and improve endurance while avoiding undue stress on the affected joints, such as aquatic therapy, are recommended.
The impact of the disease on the family must be discussed. Patients are often young women who have children or are planning to have children. Other issues include women who want their own biological children but are unable to maintain a pregnancy because of recurrent spontaneous abortions, or are advised not to become pregnant due to the teratogenicity of certain immunosuppressive medications. Patients need to understand their disease and participate in their care. In addition to avoiding the exacerbating factors, they must be reminded that SLE is multisystemic. All health providers, including dentists, should be informed about their disease. Patients may learn more about SLE from the Arthritis Foundation (see the list of resources in the section “Community Resources” at the end of this chapter).
NSAIDs are used in CV diseases. They do provide mild anti-inflammatory and analgesic effects and are helpful adjuncts for use in patients with minor manifestations such as arthralgias, fevers, and serositis. These medications should not be used in patients with renal disease and should be avoided in patients with known coronary artery disease. Complications of NSAID use are more common in SLE patients than in patients with nonrheumatic diseases, and may include aseptic meningitis and headaches.
Antimalarial drugs, especially hydroxychloroquine, are considered background therapy for all patients with lupus. They are effective nonsteroidal drugs for many patients with non-organ-threatening lupus, and even those with lupus nephritis benefit from the addition of hydroxychloroquine to their immunosuppressive regimen (Hahn et al., 2012).
These drugs are most effective for the treatment of cutaneous lesions, arthritis and arthralgia, fatigue, and serositis. Chloroquine tends to be more effective than hydroxychloroquine but because of potential toxicity is not the first choice. The chloroquines and atabrine are effective in 1 to 2 months, with peak activity in some patients not seen for up to 4 months. Generalized gastrointestinal and musculoskeletal complaints may occur, but they are reversible and often minor. The chloroquines can cause retinal damage; however, retinal damage has not been reported in patients taking recommended doses, hydroxychloroquine 6.5 mg/kg, who undergo ophthalmologic examinations every 6 to 12 months.
Corticosteroids are potent anti-inflammatory and immunosuppressive medications and are a mainstay of treatment of both minor and major manifestations. Daily oral dosing of 1 mg/kg is used in most patients with active disease. With severe disease, such as severe nephritis, high-dose intravenous pulse therapy may be warranted. The most commonly used corticosteroid preparations are prednisone and methylprednisolone. However, side effects such as hyperglycemia, hypertension, edema, premature cataracts, osteoporosis, depression and psychosis, gastric irritation, and predisposition to infections make it imperative to use the lowest dose possible. The ACR has published guidelines on the evaluation and treatment of glucocorticoid-induced osteoporosis (Grossman et al., 2010).
The use of cytotoxic or immunosuppressive drugs such as cyclophosphamide, mycophenolate mofetil, and azathioprine are typically used in the lupus nephritis patients. Recent studies have shown that mycophenolate mofetil is equivalent to cyclophosphamide, with less toxicity, and is preferred in African American patients. Treatment guidelines in lupus nephritis were reviewed in a comprehensive article (Hahn et al., 2012). Controlled trials have demonstrated the superiority of using cytotoxic drugs plus corticosteroids over the use of corticosteroids alone in lupus nephritis.
In 2011, belimumab, a human monoclonal antibody that binds B-lymphocyte stimulator, was introduced as the first new treatment for SLE since hydroxychloroquine. This medication is given parentally and is useful for patients whose lupus cannot be controlled with traditional therapies, especially if high-dose steroids have been used with diminishing effect.
Summary of Clinical Concerns
Early warnings that may indicate a flare-up of SLE include any increase in the symptoms listed in Table 36.1. Fever or chills should always alert the clinician to the possibility of an infection source, as these patients are immunocompromised. If a patient is still having flare-ups while taking oral corticosteroid therapy, a consultation with a specialist is recommended. SLE is potentially fatal, so uncertainty about the diagnosis and management should prompt a referral to a rheumatologist.
A positive test for ANA does not necessarily mean the patient has SLE. A positive ANA has a specificity for SLE of 65% and a negative test for ANA makes the diagnosis of SLE extremely unlikely. The symptoms of SLE may be vague. At times, constitutional symptoms, arthralgias, and a rash may be the only manifestations. The key to diagnosis is a comprehensive history and careful physical examination (Amissah-Arthur & Gordon, 2010; Rao & Bowman, 2013; Yildirim-Toruner & Diamond, 2011).
SJÖGREN’S SYNDROME
SS (sicca syndrome) is a slowly progressive inflammatory autoimmune disease affecting primarily the salivary and lacrimal glands. In the absence of other autoimmune diseases, the syndrome is classified as primary Sjøgren’s syndrome (pSS). It is considered secondary SS when it accompanies another connective tissue disease such as RA, SLE, or SSc (Gomes et al., 2012; Kallenberg, Vissink, Kroese, Abdulahad, & Bootsma, 2011).
Anatomy, Physiology, and Pathology
The histopathologic hallmark of SS is focal lymphocytic infiltration of the salivary glands, lacrimal glands, or extraglandular organs without structural destruction. These foci range from small foci to diffuse lesions and the extent of inflammation in a biopsy specimen is established by a focus score. At least 1 foci/4 mm2 of tissue is considered a positive test. The biopsy is usually taken from a minor salivary gland on the inside of the lower lip by an oral surgeon (Vitali, Palombi, & Cataleta, 2010).
Epidemiology
SS occurs primarily in women, with a mean age of onset between 45 and 55 years, with a female/male ratio of 9:1. The prevalence in the general population is estimated to be between 0.1% and 0.6% per the 2002 American-European Consensus criteria. The disease affects approximately 30% of patients with RA (Bowman, Ibrahim, Holmes, Hamburger, & Ainsworth, 2004; Crowson et al., 2011; Misterska-Skora, Sebastian, Dziegiel, Sebastian, & Wiland, 2013).
Diagnostic Criteria
In 2012, a classification was proposed by the American College of Rheumatology based on the expert consensus of the Sjögrens International Collaborative Clinical Alliance Cohort. Simply, SS will be diagnosed when two of the following three criteria are met:
1. Positive SS-A or SS-B or positive rheumatoid factor (RF) and a ANA ≥1:320
2. Labial salivary gland biopsy with focus score ≥1
3. Keratoconjunctivitis sicca with ocular staining score ≥3 (Huang et al., 2013; Shiboski et al., 2012)
History and Physical Examination
It is important to obtain a history of oral and ocular complaints. The patient should be asked about abnormalities of taste or smell, adherence of food to the buccal mucous membranes, difficulty chewing or swallowing, difficulty wearing dentures, and frequent ingestion of fluids. Ocular symptoms include a burning sensation, decreased tearing, a sensation of sand in the eyes, or redness. The provider should also inquire about any prior episodes of parotid enlargement. On physical examination, there may be dryness of the buccal mucous membranes and lips and fissuring of the tongue. The normal pool of saliva under the tongue, visible when the tongue is elevated, is not present. Lesions such as oral candidiasis may be noted; it occurs with increased frequency in these patients.
Gross inspection of the eyes may be unrevealing. Therefore, a referral to an ophthalmologist is often necessary so that more objective evidence of keratoconjunctivitis sicca can be obtained. Staining with fluorescein and lissamine green and then examining the cornea and conjunctiva with the use of a slit lamp should provide objective evidence of damage, usually the presence of small, superficial erosions.
Primary SS is typically more difficult to diagnose than secondary SS and the average lag time between initial symptoms and diagnosis in primary SS was 6.5 years. Approximately half of all SS patients have parotid gland enlargement, often recurrent and asymmetrical and sometimes accompanied by fever, tenderness, or erythema. Salivary gland enlargement is not pathognomonic of SS. Salivary insufficiency can be very distressing to patients. Patients may require frequent ingestion of liquids, mainly at mealtime and at night, and experience difficulty chewing and swallowing dry foods.
Abnormalities of taste and smell may also occur. Primary SS may involve many different organ systems. Musculoskeletal complaints are the most common, either arthralgias or arthritis, and patients may have renal involvement manifested as a distal renal tubular acidosis. Additional manifestations include autoimmune hepatitis or primary biliary cirrhosis (2%–4%), interstitial lung disease, and skin or vaginal dryness. Decreased vaginal secretions lead to vaginal and vulvar irritation and itching, decreased resistance to vaginal infections, and dyspareunia. Involvement of the gastrointestinal glands results in dysphagia and atrophic gastritis (Nikolov & Illei, 2009).
Disease Course
Although it is impossible to prevent the development of SS, patients need to be educated about the complications of SS and the increased risks of developing other diseases. (For more information on self-care resources, see the “Community Resources” section at the end of this chapter.) Pregnant women who have SS should be tested for antibodies to SS-A. The presence of anti-SS-A antibodies is associated with congenital heart block, transient thrombocytopenia, and rashes in newborns (neonatal lupus syndrome). In addition, the estimated risk that a patient with SS will develop malignant lymphoma is 43.8 times that of the general population (Misterska-Skora et al., 2013).
Diagnostic Studies
There are many laboratory aids for the diagnosis of SS. A complete blood count often shows anemia of chronic disease. Leukopenia has been reported in one third of patients with primary SS. Acute-phase reactants such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in most patients with primary SS.
Other laboratory studies may heighten suspicion of SS, although none are specific. Elevated serum IgM levels are present in half of the patients. ANAs are present in approximately 65% of patients. Positivity for RFs is present in 90% of patients. Low C3 and C4 levels were associated with extraglandular disease manifestation and the development of lymphoma. In addition, up to one fourth of patients will have thyroid disease and antithyroid antibodies.
Treatment Options, Expected Outcomes, and Comprehensive Management
TEACHING AND SELF-CARE
The management of patients with SS should focus on improving sicca symptoms and treating associated disorders. It is important to avoid treating patients with SS with medications such as antihistamines, cyclic antidepressants, or other anticholinergic drugs that inhibit glandular secretion. Alcohol and smoking should also be avoided. However, the most important aspect of therapeutic management is regular outpatient care by the primary care provider, ophthalmologist, rheumatologist, and dentist.
Frequent dental visits are advisable. Regular and frequent brushing with a soft-bristled toothbrush and fluoride toothpaste and the use of dental floss, oral fluoride gels, and mouthwashes that do not contain alcohol are strongly advocated for dental caries prophylaxis. Sugarless gum or candies that contain xylitol should be used to stimulate saliva production. Avoiding caffeine-containing products is also helpful. Over-the-counter products that contain xylitol, carboxymethyl cellulose, or hydroxyethyl cellulose may act as saliva substitutes.
Several over-the-counter and prescription tear substitutes are available for treating keratoconjunctivitis sicca. For patients with sensitivity to the preservatives, preservative-free solutions are available. Repeated instillation of drops may be necessary to control symptoms. A high-viscosity tear substitute may provide more comfort but can cause blurred vision. Lacriserts, a solid form of artificial tears that dissolve slowly when the eye is closed, may be useful at night. Cyclosporine drops (Restasis) modulate the immune system’s negative effect on tear production from the lacrimal glands. These drops are not tear substitutes and do not work immediately, but usually become effective within the first month. This can be combined with tear substitutes to reduce any burning that may be associated initially (Moerman, Bootsma, Kroese, & Vissink, 2013; Ng & Isenberg, 2008).
If corneal ulceration is present, referral to an ophthalmologist is necessary. Topical corticosteroids are generally avoided because corneal thinning and subsequent perforation may occur. Xerostomia may be difficult to treat and requires a multifaceted approach. Several saliva substitutes are available, but they provide only temporary relief. Increasing water intake is an effective way of eliminating the symptoms. Sugarless gum or candy may promote salivary flow through masticatory stimulation. In addition, pilocarpine (5 mg t.i.d.) or cervimeline (30 mg t.i.d.) may be of benefit for both oral and ocular complaints. It is important to recognize chronic erythematous candidiasis in these patients, who will need to be treated with antifungals (fluconazole).
Nasal and oral dryness can be treated with a humidifier in both the patient’s house and office. Vaginal dryness may be treated by frequent applications of saline soaks or Replens. Lubricants are recommended for sexual activity. Skin dryness is managed with over-the-counter emollients and moisturizers. Postmenopausal estrogen replacement therapy may also be beneficial (Haldorsen, Bjelland, Bolstad, Jonsson, & Brun, 2011).
MEDICATION REGIMEN
Treatment regimens are aimed at alleviating the symptoms of the disease, not at treating the disease itself. Methotrexate, hydroxychloroquine, and most recently rituximab have been employed depending on the severity of the organ system involvement. The management of RA or other associated disorders is not altered by the presence of SS. NSAID therapy may be useful for alleviating myalgias and arthralgia or arthritis. Hydroxychloroquine (Plaquenil), 400 mg/d, has been associated with improvement in energy level and joint and muscle pain, but no change in sicca symptoms (Rihl, Ulbricht, Schmidt, & White, 2009).
Summary of Clinical Concerns
SS is usually not a life-threatening illness, but is extremely annoying and disabling. Symptoms are usually alleviated by the recommendations mentioned previously. If the patient is still symptomatic, however, advice from or referral to a rheumatologist or ophthalmologist is warranted and may be needed to help control concomitant disease.
Making the patient comfortable is the mainstay of treatment. Although symptoms are bothersome, patients are often reluctant to mention them to the provider, especially those related to vaginal dryness and sexual activity. The provider should inquire about symptoms in a nonjudgmental, compassionate fashion. Many of the treatments are self-initiated and do not require prescriptions, but patients need to know their options, and be made aware pf safety considerations. Evaluation for associated connective tissue diseases such as RA and lupus is essential. There is a small but real risk for B-cell lymphomas. Diuretics and anticholinergic medications should be avoided secondary to decreased tears and saliva.
SYSTEMIC SCLEROSIS
SSc is a connective tissue disease characterized by autoimmunity, thickening, and fibrosis of the skin and internal organs along with widespread damage to the microvasculature. Musculoskeletal manifestations and distinctive internal organ involvement, notably of the gastrointestinal tract, lungs, heart, and kidneys, may be present.
Anatomy, Physiology, and Pathology
The primary pathologic feature of scleroderma consists of an obliterative vasculopathy of the small arteries and arterioles. Although inflammation is present early in the course, later lesions appear devoid of inflammation. This obliterative vasculopathy has critical impact on the function of the lungs, kidneys, myocardium, and gastrointestinal tract. The skin shows infiltration by collagen, fibronectin, and other macromolecules with consequent destruction of secondary skin structures, hair follicles, and sweat glands (Moore & DeSabtis, 2008).
Epidemiology
The incidence of SSc is 9 to 19 cases per million per year. The female-to-male ratio is approximately 3:1. The usual age at onset is between the third and fifth decade, with 80% of cases occurring between ages 20 and 60 years. African Americans tend to have earlier onset and increased risk, and are more likely to have diffuse SSc (dSSc). Patients with SSc are more often employed as laborers or in other less-skilled jobs and have larger ethanol intakes than control patients. Occupational exposures that may be related to development of SSc include polyvinyl chloride, coal and gold mining, and silica dust exposure. Drugs such as bleomycin have been associated with SSc-like illnesses.
Although scleroderma occurs more often in females, males appear to have a poorer prognosis. African Americans are more likely to be Scl-70 positive or have antibodies to U3-RNP, both markers for poorer survival rates than a comparable group of White patients.
Diagnostic Criteria
In 2013, the American College of Rheumatology published a new set of classification criteria replacing the older 1980 set. The new criteria offer better sensitivity and specificity and use a point system to confirm the diagnosis. In addition, this set allows for earlier diagnosis of disease and limited cutaneous systemic sclerosis (lcSSc). Patients may be classified as having SSc if they have a total score of ≥9 and do not have skin thickening sparing the fingers. Table 36.2 describes the criteria.
History and Physical Examination
Raynaud’s phenomenon is the most common initial complaint in both dcSSc and lcSSc. Typically, those patients destined to develop dcSSc have a rapid onset of skin thickening, whereas those with lcSSc have a much more gradual onset of skin tightening over months to years. Many patients experience swollen digits as an initial mild inflammatory reaction. This is then followed by tightened skin. Pruritus, arthralgia, and fatigue are common early complaints (Clarke & Werth, 2010).
The American College of Rheumatology/European League Against Rheumatism Criteria for the Classification of SSc |
ITEM | SCORE |
Skin thickening of the fingers of both hands extending to the MCP joints | 9 |
Skin thickening of the fingers; puffy fingers | 2 |
Sclerodactyly | 4 |
Fingertip lesions (count higher score), digital tip ulcers | 2 |
Fingertip pitting scars | 3 |
Telangiectasia | 2 |
Abnormal nail-fold capillaries | 2 |
Pulmonary arterial hypertension | 2 |
Interstitial lung disease (maximum score 2) | 2 |
Raynaud’s phenomenon | 3 |
SSc antibodies (maximum score 3): anticentromere, antitopoisomerase I, and anti-RNA polymerase III | 3 |
Note: It was determined that skin thickening of the fingers extending proximal to the joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nail-fold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud’s phenomenon, and SSc-related autoantibodies.
MCP, metacarpophalangeal; SSc, systemic sclerosis.
Source: Adapted from Mangat, Conron, Gabbay, and Proudman, 2010; van den Hoogen et al., 2013.
The physical examination should focus on the organ systems that may be involved. The examination should begin with vital signs, as blood pressure changes may herald renal crisis. Weight loss is often noted through serial evaluations. The skin, hair, and scalp are usually examined first. Bilateral symmetrical swelling of the fingers or hands may be seen early in the course of the disease. After several weeks to months, hard, thickened, indurated skin is seen in the digits, the dorsum of the hands, the face, and the trunk; this is pathognomonic for SSc. Loss of digital skin-fold over the dorsal interphalangeal (DIP) and proximal interphalangeal (PIP) joints may be an early clue. The provider should look for signs of Raynaud’s phenomenon, pitting of the distal finger pad, and abnormal nail capillaroscopy (see the “Raynaud’s Phenomenon” section). A thorough pulmonary and cardiac examination is required with attention to a loud P2 (Roberts-Thomson & Walker, 2011).
SSc incorporates two syndromes that are clinically different at early and late stages in the disease course. A key difference is the lag between onset of Raynaud’s phenomenon and skin involvement. Limited scleroderma (lSSc) is typified by slowly progressing skin involvement which may not start for years following onset of Raynaud’s phenomenon. Internal organ involvement occurs with similar frequencies to that of diffuse scleroderma, but the onset of involvement is delayed for years. Clinical differences between limited and diffuse disease are listed in Table 36.3.
Clinical Difference Between Limited and Diffuse Scleroderma |
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