CME #120: Cutaneous Signs of Connective Tissue Disease

C onnective tissue diseases (CTD) are a group of clinical disorders that share in common an autoimmune etiology. These include a diverse set of diseases, such as relapsing polychondritis, Sjogren? syndrome, rheumatoid arthritis, adult-onset Still? disease and mixed connective tissue disease. However, this review will focus on lupus erythematosus (LE), dermatomyositis and scleroderma, as these are the diseases most likely to present to your office. We?l provide an overview of the epidemiology, clinical presentation, diagnosis and treatment of these disorders, all of which have been exhaustively reviewed recently.1-4 Evidence suggests that both genetic and environmental factors serve to initiate and promote the autoimmune response, which is often characterized by the production of autoantibodies.5-10 As with many autoimmune diseases, CTDs display a strong predilection for women, ranging from 2:1 up to 15:1 female predominance. In addition, racial background occasionally plays a role in either severity or prevalence of disease. The wide array of overlapping clinical signs and laboratory findings among these diseases makes classification of CTD exceedingly difficult. The clinical spectrum seen in patients with lupus, dermatomyositis and scleroderma can range from skin-limited disorders to multi-systemic diseases. The skin can often be the presenting sign of illness. Thus, assessing the risk and appropriately evaluating the patient for internal organ involvement are arguably the most important roles of the dermatologist. Many times, the therapy for systemic disease will supercede any therapies that may be chosen for cutaneous involvement. It? important that the dermatologist work closely with other medical sub-specialists. When appropriate, however, dermatologists should avail themselves of topical and systemic therapies for skin disease. Lupus Erythematosus Cazenave coined the term lupus erythematosus more than a century ago,11 but much progress has been made since then in understanding the complex array of clinical manifestations of LE. Worldwide, the prevalence of systemic lupus erythematosus (SLE) has been estimated to be 17 to 48 per 100,000 people.12 This debilitating autoimmune disorder can involve virtually any organ of the body, leading to arthritis, anemia, nephritis, serositis and cardiac conduction defects. Irrespective of systemic disease, when LE involves the skin it? termed cutaneous lupus erythematosus (CLE). Not surprisingly, cutaneous disease represents one of the most common clinical signs of patients with underlying SLE, with lifetime prevalence estimated to be as high as 70%.12 Risk Factors for LE Genetics appears to be a risk factor for developing LE. Through the work of several investigators using animal or human models of LE, apoptotic factors such as Fas and Fas ligand, cytokines such as IL-2, IL-10 and TNF-alpha, immune receptors, such as FcgRIIa and the major histocompatability complex (MHC) have all been implicated in the pathogenesis of LE. SLE is associated with HLA-DR2 and HLA-DR3 while SCLE is associated with HLA-B8, HLA-DR3, HLA-DRw52, HLA-DQ1, and HLA-DQ2.13,14 SCLE has been strongly linked to deficiencies in MHC class III genes coding for complement components C2 and C4.1 Interestingly, a polymorphism in the ultraviolet (UV) light stimulated TNF-alpha promoter has been found with increased frequency in patients with SCLE.1 MHC class III genes also code for heat shock proteins, which have been previously shown to exacerbate CCLE.1 In addition to genetic factors, a number of environmental factors have been postulated to play a role in either the initiation or propagation of CLE. One commonly reported trigger is infectious agents, usually viruses. In addition, ultraviolet light (especially UVB) is known to trigger both cutaneous and systemic LE. Questioning a patient about sun sensitivity is not always a good guide, as patients often do not associate dermatologic flares with sun exposure since the response may be delayed. The presence of Ro/SSA and/or La/SSB antibodies as well as the -308A TNF-alpha promoter polymorphism all play a role in the pathogenesis of photosensitivity in CLE.1 Medications can also trigger CLE, especially the subacute form, SCLE. Although a number of medications have been associated with systemic LE, most of these are not associated with cutaneous disease. Drug-induced chronic CLE (CCLE) is very rare. In addition, a number of medications such as angiotensin-converting enzyme inhi-bitors (captopril, cilazapril), calcium channel blockers (nifedipine, diltiazem and verapamil), procainamide, sulfonylureas, and naproxen, among others, can non-specifically induce CLE due to their photosensitizing activities.1 Cigarette smoking is also associated with an increased risk of developing SLE.15 Classifying CLE Classification of the cutaneous signs of LE was developed by Gilliam, who separated skin lesions into histologically specific and non-specific.16 LE-specific lesions are further subdivided into acute CLE (ACLE), subacute CLE (SCLE) and chronic CLE (CCLE). Vigilance in understanding how to classify and diagnose CLE is important in predicting the risk of systemic disease as well as selecting appropriate therapy. The onset of ACLE is abrupt and virtually always occurs in the setting of systemic illness. The typical ACLE patient is a female in her third decade of life with an abrupt onset of a rash after sun exposure. This rash can be localized, usually to the malar region and sparing the nasolabial folds, or it can be diffuse, typically in a morbiliform or maculopapular pattern. Irrespective of location, the rash can range from mild erythema to significant edema, lasting from hours to weeks, and heals without scarring. Accompanying changes include poikiloderma, oral ulceration, scale, and a papular component. There can be diffuse thinning of scalp hair, as well as loss of the frontal hairline with evidence of hair fragility. Vitali et al., found malar rash (40%), alopecia (24%), and oral ulcers (19%) to be the most frequent dermatologic signs of SLE.17 The proximal nail fold may demonstrate telangiectasia and erythema, and there can be cuticular abnormalities. Rarely, bullae on sun-exposed skin or an erythema multiforme major-like eruption (known as Rowell? syndrome) may develop.18 About 95% of patients are positive for ANA and less frequently have antibodies to dsDNA (40% to 60%), U1RNP (35%), Smith (15% to 25%), Ro/SSA (25%), or La/SSB (10%). The presence of anti-dsDNA antibody seems to correlate with lupus nephritis, while anti-Smith antibody is the most specific for SLE.19 In general, ACLE is associated with a high risk of systemic disease and these patients are always managed in conjunction with a rheumatologist. In 1979, the term SCLE was coined by Sontheimer, Thomas and Gilliam to describe a subset of LE patients with a distinct cutaneous and serological presentation.20 Typically seen in white females of all ages, the eruption is a papulosquamous rash with either an annular/polycyclic or psoriasiform pattern. The lesions are non-scarring, lack induration and can be persistent.1 These lesions are found in a photodistributed pattern over the neck, V of the chest and back and extensor forearms; unlike ACLE, the face is less commonly affected. Extensive vacuolar degeneration can result in vesiculation at the border of the lesions. Other associated findings include alopecia (50%), malar rash, periungual telangiectasia, poikiloderma, livedo reticularis, and rarely a pityriasis-like pattern. In patients with SCLE, 70% to 80% are ANA positive, 50% to 71% Ro/SSA positive, and 30% produce rheumatoid factor (RF). The prognosis is poorly understood as this diagnosis has only recently received widespread recognition. Although up to 50% of the patients meet ACR criteria for SLE, it is estimated that only 10% to 15% will have clinically significant internal organ involvement (usually renal or CNS disease).19 CCLE is two to three times more common than SLE and represents the most common form of CLE.12 CCLE can present in multiple forms including discoid LE (DLE), hypertrophic LE, LE-lichen planus overlap, chilblain?, lupus panniculitis (lupus profundus) and lupus tumidus. The typical patient is a male or female between the ages of 20 to 40.21 DLE lesions are well demarcated, indurated, scaling erythematous plaques with adherent scale extending into hair follicles. These plaques heal centrally first, resulting in atrophy, scarring, dyspigmentation and telangiectasia. As in any chronic scarring process, DLE patients are at an increased risk of developing squamous cell carcinoma, especially in chronic mucosal lesions. Typical locations include the face (including malar regions and concha of the ears), scalp, V-area of the neck, extensor surfaces of the arms, and palmo-plantar surfaces. Scarring alopecia, a common consequence of scalp involvement, should be distinguished by the astute clinician from the increased incidence of alopecia areata in the setting of DLE. Most lesions are chronic, but 25% to 40% resolve spontaneously. It? estimated that 5% to 10% of patients who present with DLE lesions will progress to SLE. Patients at high risk for SLE are those with generalized (above and below the neck) skin lesions. Lymphadenopathy, periungual telangiectasias, Raynaud? phenomenon, fever, increasing ANA, leukopenia, hematuria, or albuminuria are also risk factors for systemic involvement. In a study of 296 patients with CCLE, Tebbe et al. reported arthralgia and antinuclear antibody (ANA) titers of greater than 1:320 to be the greatest risk factors for progression from CCLE to SLE.22 Although ANAs are detected in 40% of DLE patients, other autoantibodies are rarely seen. CLE Therapy The goal of therapy for CLE is to prevent disease progression and restore the patient? normal appearance. It? critical to educate patients on minimizing heat and sun exposure, as well as avoiding photosensitizing medications. In general, patients with SCLE and ACLE are more photosensitive than patients with CCLE. Photoprotection can be achieved with various FDA-approved clothing lines or with a broad-spectrum sunscreen or physical blockers, such as zinc oxide or micronized titanium dioxide. One small study suggests that most effective sunscreens contain both UVA (parsol 1789, mexoryl SX, mexoryl XL) and UVB protectants (octocrylene).23 Mexoryl containing products are not available in the United States. Sun blocking films may be utilized on automobile and home windows to prevent the penetration of UVA through glass. Topical or intralesional corticosteroids are sometimes effective in treating localized CCLE as well as CLE involving the scalp. For telangiectasia, the pulsed-dye laser appears to be a treatment with few side effects and a clearance rate approaching 70%. Scarring of CCLE can be addressed using a carbon-dioxide laser or dermabrasion, although extreme care should be taken due to the tendency for DLE lesions to Koebnerize. If topical agents fail, antimalarials are the drug of choice for SCLE or CCLE. Hydroxychloroquine (<6.5 mg/kg/day) or chloroquine (<4.5 mg/kg/day) can be used with success in 70% to 80% of cases.17 A conservative recommendation for annual eye examinations is typically made, although recently published official guidelines recommend this frequency for only the high-risk patients (>60 yr old, >5 years use, doses in excess of those suggested, liver disease, renal disease, retinal disease).24 This treatment is slow in onset, and patients should be forewarned that benefit may not be noticed for 6 to 8 weeks for chloroquine and 3 to 4 months for hydroxychloroquine. Smoking should be avoided as this diminishes the efficacy of antimalarial drugs. In patients with SCLE, a medication-induced etiology should be examined, as thiazide diuretics, calcium channel blockers, terbinafine, and rarely ACE inhibitors and statin drugs, have been reported to trigger SCLE. Corticosteroids are often used to control ACLE, but have only a temporizing role for SCLE and should not be used for DLE. Thalidomide has been shown to be an effective therapy for DLE and SCLE, with a 60% to 80% response rate. CCLE has been treated with oral retinoids and auranofin, and classical immunosuppressants (i.e. azathioprine, cyclosporine, methotrexate, cyclophosphamide) are also used in refractory cases with systemic involvement. Finally, encourage patients to join a support group by contacting the lupus foundation (www.lupus.org). Dermatomyositis Classical dermatomyositis (DM) is a multisystem inflammatory disorder of autoimmune etiology characterized by a cutaneous eruption in the setting of symmetric proximal, extensor myopathy. DM can present with a wide spectrum of clinical findings and can be subtyped as amyopathic DM, clinically amyopathic DM, or classic DM.3 Amyopathic DM describes a group of patients with biopsy-proven classic DM skin signs that last at least 6 months without clinical evidence of muscle weakness, serological evidence of muscle enzyme abnormalities or biopsy evidence of muscle inflammation. This diagnosis can not be established if patients have undergone recent immunosuppressive therapy of 2 months or more within the first 6 months of onset of cutaneous disease. Coincidental appearance of classic skin findings with use of medications known to generate DM-like cutaneous changes (hydroxyurea or the statin class of lipid lowering agents) also precludes a diagnosis of amyopathic DM. Patients who have more rigorous muscle testing (laboratory, electrophysiologic, or radiologic evaluation) are found to have positive test results representing subclinical myositis are best classified as hypomyopathic DM. The term clinically amyopathic DM includes amyopathic DM and hypomyopathic DM since, in both entities, the cutaneous lesions represent the primary clinical finding. In classic DM, patients present with hallmark skin findings of DM, as well as clinical and objective evidence of muscle inflammation. Because DM can occur in the absence of muscle disease, the criteria of Bohan and Peter25 were revised by Sontheimer to define diagnostic criteria for the cutaneous findings, which are seen in all subtypes of the dermatomyositis spectrum.3 Classically, patients present with a heliotrope rash, erythematous scaling papules over the knuckles (Gottron? papules), or erythematous macules or patches overlying bony eminences, such as the knuckles, elbows, knees or ankles (Gottron? sign). Scaling plaques on the scalp (and other areas), photodistributed poikiloderma, a scaling hand dermatitis (?echanic? hands?, calcinosis cutis and periungual telangiectasias are also found. These lesions are commonly confused with CLE, but the presence of pruritus or burning, poikiloderma, and scalp involvement favor a diagnosis of dermatomyositis over lupus. Classic DM patients are positive for ANA in 40% to 60% of all cases. So-called antisynthetase autoantibodies (such as Jo-1) are specific for DM but only found in 15% of patients.26 The Mi-2 autoantibody is found in 10% to 21% of patients and is also very specific for DM.26 Recent research suggests that antibodies against two novel targets (155 kd and Se) may define the cohort of patients with clinically amyopathic disease.27 In addition to cutaneous findings, the dermatologist needs to assess for the presence of muscle disease. This can be done by measuring muscle strength, as well as performing a muscle biopsy, EMG or MRI. How far to go in this pursuit is controversial, due to the unclear clinical significance of small changes on MRI or EMG. Serum levels of muscle enzymes (especially CPK and aldolase) can also be useful, although these are not 100% sensitive. Common Clinical Associations of DM The two most important clinical associations with dermatomyositis are malignancy and interstitial pulmonary disease. The increased risk of malignancy (from 1.7 to 6.5 fold) is highest in the first 1 to 2 years after diagnosis but seems to remain slightly elevated for many years.28 Certain cancers (ovarian in women and stomach and lymphoma in men) seem to predominate, although most of the common types of cancer can be seen. It is unclear if the increased cancer risk also pertains to patients with amyopathic disease, although preliminary data suggest that this may be the case. Interstitial lung disease is seen in 5% to 40% of patients, and it appears that this may be the case with the amyopathic group as well. Non-productive cough and dyspnea on exertion are the most common symptoms. Pulmonary function tests show a restrictive pattern. Antisynthetase antibodies, such as Jo-1, may confer an increased risk of arthritis, Raynaud? phenomenon and interstitial lung disease in patients with classic DM. Lung disease is usually chronic and slowly progressive, but can present acutely with respiratory distress and possible death. It should be remembered that DM is a multisystem autoimmune disease and can also lead to significant internal organ involvement including joints, heart, gastrointestinal tract and eyes. Although juvenile DM patients are not at an increased risk for malignancy, these patients often develop calcinosis at sites of trauma. In addition, a non-erosive arthritis involving the knees, elbows and fingers can develop in 20% to 65% of juvenile DM patients, affecting the classic and clinically amyopathic types. Managing and Treating DM Once you diagnose a patient with dermatomyositis, you?l first need to monitor the patient for systemic complications. The method of searching for malignancy is controversial, with some authors suggesting age appropriate or symptom targeted evaluations and others recommending full-body imaging. Because the window for high risk of developing malignancy is short (1 to 2 years), some suggest that full body CT scans are cost-effective. The fact that ovarian cancer is overrepresented and difficult to diagnose, along with the recent observation that only CT scanning was able to diagnose an occult malignancy in a study of 40 patients with dermatomyositis and cancer, supports this recommendation.29 The use of serological markers such as CA-125 or CEA is controversial and presently seems appropriate only for following patients with known malignancy. The difficulties with assessing muscle involvement have been discussed, but at the very least the clinician should take a careful history (difficulty arising from a chair, ascending stairs, reaching high for objects, a change in voice tone), perform a complete muscle strength examination and assess serum muscle enzyme levels every 3 months. Lung disease should be assessed by pulmonary function tests and/or chest X-rays at least annually or with greater frequency in the presence of symptoms. Treatment of dermatomyositis depends on the extent of disease. For patients with muscle disease, the first-line therapy is oral or intravenous pulse corticosteroids. Steroid-sparing agents have also been used, such as methotrexate, cyclosporine, and high-dose intravenous immunoglobulin. There? a general belief that corticosteroids should be used for a minimum of 2 years utilizing a slow taper in order to prevent smoldering, refractory muscle disease. Chlorambucil (Leukeran) may also be used in refractory cases to control either skin or muscle disease activity. Instruct patients with cutaneous disease to follow strict UV avoidance measures and to use sunscreens with broad-spectrum activity. Topical steroids and/or oral antihistamines may offer symptomatic relief of pruritus or scalp DM. Topical immunomodulators, such as tacrolimus (Protopic) or pimecrolimus (Elidel), can be helpful. The antimalarials are less helpful in DM than in CLE, but can be tried. A recent report suggests that DM patients may be more subject to adverse cutaneous reactions to antimalarials.30 Dapsone, mycophenolate mofetil (CellCept), methotrexate, and thalidomide (Thalomid) have all been used with variable results. Scleroderma Scleroderma represents a diverse array of disorders unified by sclerosis of the skin. It? difficult to diagnose scleroderma, as there are many other disorders that can demonstrate cutaneous sclerosis, such as scleredema, myxedema, scleromyxedema, nephrogenic fibrosing dermatopathy and eosinophilic fasciitis. Various genetic disorders (Progeria), metabolic diseases (porphyria, lipodystrophy) and paraneoplastic syndromes can also result in cutaneous sclerosis. Toxins (rapseed oil), medications (bleomycin) and even external trauma (vibration) can result is scleroderma-like signs. True scleroderma occurs in two distinct categories ?localized or systemic. Localized scleroderma, also termed morphea, includes plaque (56%), generalized (13%), linear (20%) and deep forms (11%). The typical patient presents with an insidious onset of well-delineated indurated plaques. Often a violaceous or erythematous border, the so-called lilac ring, is present early on in the course. This halo represents active inflammation; however, as the disease progresses, this is replaced by prominent sclerosis with central atrophy, which gives the skin an ivory appearance. Some lesions show only hyperpigmentation without sclerosis, and these can show thickened collagen limited only to the upper dermis; hence, these lesions have been termed "superficial morphea." Many lesions can resemble lichen sclerosis et atrophicus (LS&A), and some authors believe that the lesions of so-called superficial morphea and LS&A lie along a spectrum. Lesions can be found in one or two anatomic sites throughout the body, but usually spare the face. An exception to this is in linear morphea, which afflicts patients in the pediatric population with no sex predilection, and can involve the face and scalp. This presentation is known as en coup de sabre, and typically is unilateral most commonly on the paramedian forehead. En coup de sabre can be associated with other clinical findings, such as alopecia, ptosis, ocular dysfunction, uveitis and dental anomalies. Morphea can also be complicated by systemic findings, such as arthralgia, and rarely esophageal dysmotility. Report-ed associations include lichen planus, vitiligo, alopecia areata, nephritis and biliary cirrhosis. Antinuclear antibodies are positive in 46% to 80% of patients, usually in a homogenous pattern. Antihistone and anti ssDNA antibodies can be detected with a similar frequency, although their significance remains unknown. Serum rheumatoid factor can be detected in 25% of cases. Eosinophilia has been reported in patients with linear and generalized morphea, and may correlate with disease severity. Approach autoantibody markers with caution, however, as the presence of these markers in localized scleroderma is of dubious value. These patients have virtually no risk of systemic disease. Prognosis of skin disease is generally quite good, with lesions tending to show spontaneous regression over several years; linear morphea and generalized morphea are the exceptions, as they can be chronic and progressive. Managing and Treating Morphea In managing a patient with morphea, the most important thing you can do is reassure the patient that they will not progress to systemic sclerosis. In linear and deep types of morphea, the importance of physical therapy in preventing joint deformities and contractures cannot be overestimated. Beyond this, the treatment of morphea has been disappointing. Pruritus can be controlled with dry skin care and topical (pramoxine, menthol) or oral (antihistamines) therapy. Intralesional corticosteroids can be used on localized lesions. A small, open-label study suggested that calcipotriene (Dovonex) under occlusion can be effective.31 Recent evidence from a number of centers suggests that UVA (either broadband or UVA1) may be effective, although no controlled studies have been published.32 Rapidly progressive disease, especially in children, is often treated with high-dose corticosteroids in the presence or absence of methotrexate.33 In general, the role of immunosuppressants for this disorder is questionable. Oral calcitriol (Rocaltrol), d-penicillamine (Cuprimine), interferon gamma (Actimmune), and phenytoin (Dilantin) are probably not effective. Treating Systemic Sclerosis Systemic sclerosis (SSc) is divided into limited and diffuse forms.34 The hallmarks of both diseases are Raynaud? phenomenon (present in >95% of patients), positive ANA (>90%), and sclerosis of the hands and fingers. A mask-like facies with decreased oral aperture is sometimes a feature. The nose may appear pinched, and the lips are thin. Ridging and skin tightening of the neck is especially apparent during extension. Abnormal periungual capillary patterns are seen in >90% of patients and can help in distinguishing this disorder from morphea or non-rheumatic causes of cutaneous sclerosis. Pteryguim inversum unguis and calcinosis cutis can also be seen. The fingers can develop painful digital ulcers and pits, secondary to the vasculopathy associated with this disorder. Limited SSc (lSSc) is present in 60% of cases of SSc. Formerly termed CREST, this disorder is characterized by involvement of the forearms and hands and variable involvement on the neck and perioral region. Often, lSSc can present for many years with puffy, edematous skin without significant sclerosis. Often the first symptom is a long history of Raynaud? phenomenon. The disease can be associated with esophageal dysmotility, calcinosis and telangiectasias. Although lSSc generally has a good prognosis, these patients can suffer from isolated pulmonary hypertension in the absence of pulmonary fibrosis. This occurs in 10% to 15% of patients. These patients will rarely (5%) suffer from renal disease. Diffuse SSc (dSSc) can be diagnosed with truncal or proximal limb involvement. These patients are at higher risk for pulmonary fibrosis (70%) and pulmonary hypertension (40%). Renal disease (manifested as proteinuria, azotemia, mild hypertension or renal insufficiency) occurs in 10% to 40% of patients, with patients experiencing so-called ?enal crisis?10% of the time. The latter is a medical emergency in which patients present with hypertension and hemolytic anemia. Gastrointestinal involvement can occur at any level of the GI tract, resulting in reflux, dysphagia, so-called watermelon stomach, malabsorption, diarrhea and constipation. Patients can also have pericardial effusions, conduction defects, and cardiac ischemia. Weakness (even with mild elevation of muscle enzymes) and arthralgias can also be seen. Much progress has been made in attempting to correlate autoantibody profiles with prognosis in patients with SSc. For patients with lSSc, anti-centromere antibodies (present in 40%) tend to correlate with calcinosis and vasculopathy (represented by telangiectasias and digital ischemic loss), but in general are associated with a good prognosis. lSSc patients with anti-Th/To (RNAse P) tend to have the odd finding of pulmonary fibrosis and may represent the small subset at risk for renal crisis. The PM-Scl (PM-1) antibody is found in the rare subset of lSSc patients with a myositis overlap. Patients with dSSc will have a positive autoantibody (anti Scl70, anti-fibrillarin, or anti-RNA polymerase I,II,III) 80% of the time. In the dSSc patients, Scl70 (30%) correlates with pulmonary fibrosis and cardiac involvement; anti-fibrillarin (6% to 10%) can be found in patients at risk for isolated pulmonary hypertension; anti-RNA polymerase I, II, III (40%) is associated with rapidly progressive skin disease and renal disease and thus has a poor prognosis. Thus, a careful clinical examination and proper use of autoantibody profiling can help you diagnos lSSc or dSSc, and can also help you determine which patients are at risk for certain systemic problems. ACE-inhibitors have dramatically im-proved the survival of patients with renal crisis, and now cardiopulmonary disease continues to be the leading cause of mortality in this population. In general, patients with lSSc should have quarterly blood pressure monitoring and annual pulmonary function tests, in addition to a complete review of systems. Patients at high risk of developing pulmonary hypertension (isolated decrease in DLCO, anti-fibrillarin antibodies, cough or dyspnea) can then be effectively screened with echocardiograms. Patients with dSSc should have a home blood pressure monitor and be screened quarterly with basic chemistry panels and urinalyses. This is a multi-disciplinary approach that can involve rheumatologists, pulmonologists, nephrologists and gastroenterologists. In general, the search for a treatment for systemic sclerosis has been disappointing. The treatments for GI, renal and pulmonary complications of the disease can be effective and are reviewed elsewhere.4 However, controlled trials have not definitively supported any therapy for altering the overall course of skin disease in SSc. Management is similar to that of morphea. Treatment of calcinosis cutis is difficult, although agents such as aluminum hydroxide (Maalox, Alu-Cap), warfarin (Coumadin), colchicine (Probenecid & Colchicine) and surgical excision have been used with marginal success; the most important thing is to prevent infection of the lesions. Cyclosporine A (Gengraf, Neoral, Sandimmune), methotrexate, minocycline (Dynacin, Minocin), and thalidomide all have potential benefit. In general, immunosuppression has been disappointing, as has the use of d-penicillamine, relaxin, interferon gamma, colchicine, photopheresis, and plasmapheresis. Patient education is of critical importance in SSc. Patients should contact the Scleroderma foundation at (800) 422-1113 or www.scleroderma.org for more information about support groups and invaluable literature about the disease. Patients frustrated with current treatment options may contact the Scleroderma Clinical Trials Consortium to learn about and possibly participate in ongoing clinical trials (www.sctc-online.org). Looking Ahead Current molecular techniques, such as high-throughput gene and protein analysis, are only now revealing possible gene products involved in the pathogenesis of CTD. This knowledge, along with the advent of biologic agents that are able to specifically target secreted molecules, cell types, or intracellular signaling molecules, offers some hope for patients suffering from CTD. These agents hold out the promise that we, as dermatologists, may someday be in a position to offer not only prognostic information but a real hope for cure for this unfortunate group of patients.

C onnective tissue diseases (CTD) are a group of clinical disorders that share in common an autoimmune etiology. These include a diverse set of diseases, such as relapsing polychondritis, Sjogren? syndrome, rheumatoid arthritis, adult-onset Still? disease and mixed connective tissue disease. However, this review will focus on lupus erythematosus (LE), dermatomyositis and scleroderma, as these are the diseases most likely to present to your office. We?l provide an overview of the epidemiology, clinical presentation, diagnosis and treatment of these disorders, all of which have been exhaustively reviewed recently.1-4 Evidence suggests that both genetic and environmental factors serve to initiate and promote the autoimmune response, which is often characterized by the production of autoantibodies.5-10 As with many autoimmune diseases, CTDs display a strong predilection for women, ranging from 2:1 up to 15:1 female predominance. In addition, racial background occasionally plays a role in either severity or prevalence of disease. The wide array of overlapping clinical signs and laboratory findings among these diseases makes classification of CTD exceedingly difficult. The clinical spectrum seen in patients with lupus, dermatomyositis and scleroderma can range from skin-limited disorders to multi-systemic diseases. The skin can often be the presenting sign of illness. Thus, assessing the risk and appropriately evaluating the patient for internal organ involvement are arguably the most important roles of the dermatologist. Many times, the therapy for systemic disease will supercede any therapies that may be chosen for cutaneous involvement. It? important that the dermatologist work closely with other medical sub-specialists. When appropriate, however, dermatologists should avail themselves of topical and systemic therapies for skin disease. Lupus Erythematosus Cazenave coined the term lupus erythematosus more than a century ago,11 but much progress has been made since then in understanding the complex array of clinical manifestations of LE. Worldwide, the prevalence of systemic lupus erythematosus (SLE) has been estimated to be 17 to 48 per 100,000 people.12 This debilitating autoimmune disorder can involve virtually any organ of the body, leading to arthritis, anemia, nephritis, serositis and cardiac conduction defects. Irrespective of systemic disease, when LE involves the skin it? termed cutaneous lupus erythematosus (CLE). Not surprisingly, cutaneous disease represents one of the most common clinical signs of patients with underlying SLE, with lifetime prevalence estimated to be as high as 70%.12 Risk Factors for LE Genetics appears to be a risk factor for developing LE. Through the work of several investigators using animal or human models of LE, apoptotic factors such as Fas and Fas ligand, cytokines such as IL-2, IL-10 and TNF-alpha, immune receptors, such as FcgRIIa and the major histocompatability complex (MHC) have all been implicated in the pathogenesis of LE. SLE is associated with HLA-DR2 and HLA-DR3 while SCLE is associated with HLA-B8, HLA-DR3, HLA-DRw52, HLA-DQ1, and HLA-DQ2.13,14 SCLE has been strongly linked to deficiencies in MHC class III genes coding for complement components C2 and C4.1 Interestingly, a polymorphism in the ultraviolet (UV) light stimulated TNF-alpha promoter has been found with increased frequency in patients with SCLE.1 MHC class III genes also code for heat shock proteins, which have been previously shown to exacerbate CCLE.1 In addition to genetic factors, a number of environmental factors have been postulated to play a role in either the initiation or propagation of CLE. One commonly reported trigger is infectious agents, usually viruses. In addition, ultraviolet light (especially UVB) is known to trigger both cutaneous and systemic LE. Questioning a patient about sun sensitivity is not always a good guide, as patients often do not associate dermatologic flares with sun exposure since the response may be delayed. The presence of Ro/SSA and/or La/SSB antibodies as well as the -308A TNF-alpha promoter polymorphism all play a role in the pathogenesis of photosensitivity in CLE.1 Medications can also trigger CLE, especially the subacute form, SCLE. Although a number of medications have been associated with systemic LE, most of these are not associated with cutaneous disease. Drug-induced chronic CLE (CCLE) is very rare. In addition, a number of medications such as angiotensin-converting enzyme inhi-bitors (captopril, cilazapril), calcium channel blockers (nifedipine, diltiazem and verapamil), procainamide, sulfonylureas, and naproxen, among others, can non-specifically induce CLE due to their photosensitizing activities.1 Cigarette smoking is also associated with an increased risk of developing SLE.15 Classifying CLE Classification of the cutaneous signs of LE was developed by Gilliam, who separated skin lesions into histologically specific and non-specific.16 LE-specific lesions are further subdivided into acute CLE (ACLE), subacute CLE (SCLE) and chronic CLE (CCLE). Vigilance in understanding how to classify and diagnose CLE is important in predicting the risk of systemic disease as well as selecting appropriate therapy. The onset of ACLE is abrupt and virtually always occurs in the setting of systemic illness. The typical ACLE patient is a female in her third decade of life with an abrupt onset of a rash after sun exposure. This rash can be localized, usually to the malar region and sparing the nasolabial folds, or it can be diffuse, typically in a morbiliform or maculopapular pattern. Irrespective of location, the rash can range from mild erythema to significant edema, lasting from hours to weeks, and heals without scarring. Accompanying changes include poikiloderma, oral ulceration, scale, and a papular component. There can be diffuse thinning of scalp hair, as well as loss of the frontal hairline with evidence of hair fragility. Vitali et al., found malar rash (40%), alopecia (24%), and oral ulcers (19%) to be the most frequent dermatologic signs of SLE.17 The proximal nail fold may demonstrate telangiectasia and erythema, and there can be cuticular abnormalities. Rarely, bullae on sun-exposed skin or an erythema multiforme major-like eruption (known as Rowell? syndrome) may develop.18 About 95% of patients are positive for ANA and less frequently have antibodies to dsDNA (40% to 60%), U1RNP (35%), Smith (15% to 25%), Ro/SSA (25%), or La/SSB (10%). The presence of anti-dsDNA antibody seems to correlate with lupus nephritis, while anti-Smith antibody is the most specific for SLE.19 In general, ACLE is associated with a high risk of systemic disease and these patients are always managed in conjunction with a rheumatologist. In 1979, the term SCLE was coined by Sontheimer, Thomas and Gilliam to describe a subset of LE patients with a distinct cutaneous and serological presentation.20 Typically seen in white females of all ages, the eruption is a papulosquamous rash with either an annular/polycyclic or psoriasiform pattern. The lesions are non-scarring, lack induration and can be persistent.1 These lesions are found in a photodistributed pattern over the neck, V of the chest and back and extensor forearms; unlike ACLE, the face is less commonly affected. Extensive vacuolar degeneration can result in vesiculation at the border of the lesions. Other associated findings include alopecia (50%), malar rash, periungual telangiectasia, poikiloderma, livedo reticularis, and rarely a pityriasis-like pattern. In patients with SCLE, 70% to 80% are ANA positive, 50% to 71% Ro/SSA positive, and 30% produce rheumatoid factor (RF). The prognosis is poorly understood as this diagnosis has only recently received widespread recognition. Although up to 50% of the patients meet ACR criteria for SLE, it is estimated that only 10% to 15% will have clinically significant internal organ involvement (usually renal or CNS disease).19 CCLE is two to three times more common than SLE and represents the most common form of CLE.12 CCLE can present in multiple forms including discoid LE (DLE), hypertrophic LE, LE-lichen planus overlap, chilblain?, lupus panniculitis (lupus profundus) and lupus tumidus. The typical patient is a male or female between the ages of 20 to 40.21 DLE lesions are well demarcated, indurated, scaling erythematous plaques with adherent scale extending into hair follicles. These plaques heal centrally first, resulting in atrophy, scarring, dyspigmentation and telangiectasia. As in any chronic scarring process, DLE patients are at an increased risk of developing squamous cell carcinoma, especially in chronic mucosal lesions. Typical locations include the face (including malar regions and concha of the ears), scalp, V-area of the neck, extensor surfaces of the arms, and palmo-plantar surfaces. Scarring alopecia, a common consequence of scalp involvement, should be distinguished by the astute clinician from the increased incidence of alopecia areata in the setting of DLE. Most lesions are chronic, but 25% to 40% resolve spontaneously. It? estimated that 5% to 10% of patients who present with DLE lesions will progress to SLE. Patients at high risk for SLE are those with generalized (above and below the neck) skin lesions. Lymphadenopathy, periungual telangiectasias, Raynaud? phenomenon, fever, increasing ANA, leukopenia, hematuria, or albuminuria are also risk factors for systemic involvement. In a study of 296 patients with CCLE, Tebbe et al. reported arthralgia and antinuclear antibody (ANA) titers of greater than 1:320 to be the greatest risk factors for progression from CCLE to SLE.22 Although ANAs are detected in 40% of DLE patients, other autoantibodies are rarely seen. CLE Therapy The goal of therapy for CLE is to prevent disease progression and restore the patient? normal appearance. It? critical to educate patients on minimizing heat and sun exposure, as well as avoiding photosensitizing medications. In general, patients with SCLE and ACLE are more photosensitive than patients with CCLE. Photoprotection can be achieved with various FDA-approved clothing lines or with a broad-spectrum sunscreen or physical blockers, such as zinc oxide or micronized titanium dioxide. One small study suggests that most effective sunscreens contain both UVA (parsol 1789, mexoryl SX, mexoryl XL) and UVB protectants (octocrylene).23 Mexoryl containing products are not available in the United States. Sun blocking films may be utilized on automobile and home windows to prevent the penetration of UVA through glass. Topical or intralesional corticosteroids are sometimes effective in treating localized CCLE as well as CLE involving the scalp. For telangiectasia, the pulsed-dye laser appears to be a treatment with few side effects and a clearance rate approaching 70%. Scarring of CCLE can be addressed using a carbon-dioxide laser or dermabrasion, although extreme care should be taken due to the tendency for DLE lesions to Koebnerize. If topical agents fail, antimalarials are the drug of choice for SCLE or CCLE. Hydroxychloroquine (<6.5 mg/kg/day) or chloroquine (<4.5 mg/kg/day) can be used with success in 70% to 80% of cases.17 A conservative recommendation for annual eye examinations is typically made, although recently published official guidelines recommend this frequency for only the high-risk patients (>60 yr old, >5 years use, doses in excess of those suggested, liver disease, renal disease, retinal disease).24 This treatment is slow in onset, and patients should be forewarned that benefit may not be noticed for 6 to 8 weeks for chloroquine and 3 to 4 months for hydroxychloroquine. Smoking should be avoided as this diminishes the efficacy of antimalarial drugs. In patients with SCLE, a medication-induced etiology should be examined, as thiazide diuretics, calcium channel blockers, terbinafine, and rarely ACE inhibitors and statin drugs, have been reported to trigger SCLE. Corticosteroids are often used to control ACLE, but have only a temporizing role for SCLE and should not be used for DLE. Thalidomide has been shown to be an effective therapy for DLE and SCLE, with a 60% to 80% response rate. CCLE has been treated with oral retinoids and auranofin, and classical immunosuppressants (i.e. azathioprine, cyclosporine, methotrexate, cyclophosphamide) are also used in refractory cases with systemic involvement. Finally, encourage patients to join a support group by contacting the lupus foundation (www.lupus.org). Dermatomyositis Classical dermatomyositis (DM) is a multisystem inflammatory disorder of autoimmune etiology characterized by a cutaneous eruption in the setting of symmetric proximal, extensor myopathy. DM can present with a wide spectrum of clinical findings and can be subtyped as amyopathic DM, clinically amyopathic DM, or classic DM.3 Amyopathic DM describes a group of patients with biopsy-proven classic DM skin signs that last at least 6 months without clinical evidence of muscle weakness, serological evidence of muscle enzyme abnormalities or biopsy evidence of muscle inflammation. This diagnosis can not be established if patients have undergone recent immunosuppressive therapy of 2 months or more within the first 6 months of onset of cutaneous disease. Coincidental appearance of classic skin findings with use of medications known to generate DM-like cutaneous changes (hydroxyurea or the statin class of lipid lowering agents) also precludes a diagnosis of amyopathic DM. Patients who have more rigorous muscle testing (laboratory, electrophysiologic, or radiologic evaluation) are found to have positive test results representing subclinical myositis are best classified as hypomyopathic DM. The term clinically amyopathic DM includes amyopathic DM and hypomyopathic DM since, in both entities, the cutaneous lesions represent the primary clinical finding. In classic DM, patients present with hallmark skin findings of DM, as well as clinical and objective evidence of muscle inflammation. Because DM can occur in the absence of muscle disease, the criteria of Bohan and Peter25 were revised by Sontheimer to define diagnostic criteria for the cutaneous findings, which are seen in all subtypes of the dermatomyositis spectrum.3 Classically, patients present with a heliotrope rash, erythematous scaling papules over the knuckles (Gottron? papules), or erythematous macules or patches overlying bony eminences, such as the knuckles, elbows, knees or ankles (Gottron? sign). Scaling plaques on the scalp (and other areas), photodistributed poikiloderma, a scaling hand dermatitis (?echanic? hands?, calcinosis cutis and periungual telangiectasias are also found. These lesions are commonly confused with CLE, but the presence of pruritus or burning, poikiloderma, and scalp involvement favor a diagnosis of dermatomyositis over lupus. Classic DM patients are positive for ANA in 40% to 60% of all cases. So-called antisynthetase autoantibodies (such as Jo-1) are specific for DM but only found in 15% of patients.26 The Mi-2 autoantibody is found in 10% to 21% of patients and is also very specific for DM.26 Recent research suggests that antibodies against two novel targets (155 kd and Se) may define the cohort of patients with clinically amyopathic disease.27 In addition to cutaneous findings, the dermatologist needs to assess for the presence of muscle disease. This can be done by measuring muscle strength, as well as performing a muscle biopsy, EMG or MRI. How far to go in this pursuit is controversial, due to the unclear clinical significance of small changes on MRI or EMG. Serum levels of muscle enzymes (especially CPK and aldolase) can also be useful, although these are not 100% sensitive. Common Clinical Associations of DM The two most important clinical associations with dermatomyositis are malignancy and interstitial pulmonary disease. The increased risk of malignancy (from 1.7 to 6.5 fold) is highest in the first 1 to 2 years after diagnosis but seems to remain slightly elevated for many years.28 Certain cancers (ovarian in women and stomach and lymphoma in men) seem to predominate, although most of the common types of cancer can be seen. It is unclear if the increased cancer risk also pertains to patients with amyopathic disease, although preliminary data suggest that this may be the case. Interstitial lung disease is seen in 5% to 40% of patients, and it appears that this may be the case with the amyopathic group as well. Non-productive cough and dyspnea on exertion are the most common symptoms. Pulmonary function tests show a restrictive pattern. Antisynthetase antibodies, such as Jo-1, may confer an increased risk of arthritis, Raynaud? phenomenon and interstitial lung disease in patients with classic DM. Lung disease is usually chronic and slowly progressive, but can present acutely with respiratory distress and possible death. It should be remembered that DM is a multisystem autoimmune disease and can also lead to significant internal organ involvement including joints, heart, gastrointestinal tract and eyes. Although juvenile DM patients are not at an increased risk for malignancy, these patients often develop calcinosis at sites of trauma. In addition, a non-erosive arthritis involving the knees, elbows and fingers can develop in 20% to 65% of juvenile DM patients, affecting the classic and clinically amyopathic types. Managing and Treating DM Once you diagnose a patient with dermatomyositis, you?l first need to monitor the patient for systemic complications. The method of searching for malignancy is controversial, with some authors suggesting age appropriate or symptom targeted evaluations and others recommending full-body imaging. Because the window for high risk of developing malignancy is short (1 to 2 years), some suggest that full body CT scans are cost-effective. The fact that ovarian cancer is overrepresented and difficult to diagnose, along with the recent observation that only CT scanning was able to diagnose an occult malignancy in a study of 40 patients with dermatomyositis and cancer, supports this recommendation.29 The use of serological markers such as CA-125 or CEA is controversial and presently seems appropriate only for following patients with known malignancy. The difficulties with assessing muscle involvement have been discussed, but at the very least the clinician should take a careful history (difficulty arising from a chair, ascending stairs, reaching high for objects, a change in voice tone), perform a complete muscle strength examination and assess serum muscle enzyme levels every 3 months. Lung disease should be assessed by pulmonary function tests and/or chest X-rays at least annually or with greater frequency in the presence of symptoms. Treatment of dermatomyositis depends on the extent of disease. For patients with muscle disease, the first-line therapy is oral or intravenous pulse corticosteroids. Steroid-sparing agents have also been used, such as methotrexate, cyclosporine, and high-dose intravenous immunoglobulin. There? a general belief that corticosteroids should be used for a minimum of 2 years utilizing a slow taper in order to prevent smoldering, refractory muscle disease. Chlorambucil (Leukeran) may also be used in refractory cases to control either skin or muscle disease activity. Instruct patients with cutaneous disease to follow strict UV avoidance measures and to use sunscreens with broad-spectrum activity. Topical steroids and/or oral antihistamines may offer symptomatic relief of pruritus or scalp DM. Topical immunomodulators, such as tacrolimus (Protopic) or pimecrolimus (Elidel), can be helpful. The antimalarials are less helpful in DM than in CLE, but can be tried. A recent report suggests that DM patients may be more subject to adverse cutaneous reactions to antimalarials.30 Dapsone, mycophenolate mofetil (CellCept), methotrexate, and thalidomide (Thalomid) have all been used with variable results. Scleroderma Scleroderma represents a diverse array of disorders unified by sclerosis of the skin. It? difficult to diagnose scleroderma, as there are many other disorders that can demonstrate cutaneous sclerosis, such as scleredema, myxedema, scleromyxedema, nephrogenic fibrosing dermatopathy and eosinophilic fasciitis. Various genetic disorders (Progeria), metabolic diseases (porphyria, lipodystrophy) and paraneoplastic syndromes can also result in cutaneous sclerosis. Toxins (rapseed oil), medications (bleomycin) and even external trauma (vibration) can result is scleroderma-like signs. True scleroderma occurs in two distinct categories ?localized or systemic. Localized scleroderma, also termed morphea, includes plaque (56%), generalized (13%), linear (20%) and deep forms (11%). The typical patient presents with an insidious onset of well-delineated indurated plaques. Often a violaceous or erythematous border, the so-called lilac ring, is present early on in the course. This halo represents active inflammation; however, as the disease progresses, this is replaced by prominent sclerosis with central atrophy, which gives the skin an ivory appearance. Some lesions show only hyperpigmentation without sclerosis, and these can show thickened collagen limited only to the upper dermis; hence, these lesions have been termed "superficial morphea." Many lesions can resemble lichen sclerosis et atrophicus (LS&A), and some authors believe that the lesions of so-called superficial morphea and LS&A lie along a spectrum. Lesions can be found in one or two anatomic sites throughout the body, but usually spare the face. An exception to this is in linear morphea, which afflicts patients in the pediatric population with no sex predilection, and can involve the face and scalp. This presentation is known as en coup de sabre, and typically is unilateral most commonly on the paramedian forehead. En coup de sabre can be associated with other clinical findings, such as alopecia, ptosis, ocular dysfunction, uveitis and dental anomalies. Morphea can also be complicated by systemic findings, such as arthralgia, and rarely esophageal dysmotility. Report-ed associations include lichen planus, vitiligo, alopecia areata, nephritis and biliary cirrhosis. Antinuclear antibodies are positive in 46% to 80% of patients, usually in a homogenous pattern. Antihistone and anti ssDNA antibodies can be detected with a similar frequency, although their significance remains unknown. Serum rheumatoid factor can be detected in 25% of cases. Eosinophilia has been reported in patients with linear and generalized morphea, and may correlate with disease severity. Approach autoantibody markers with caution, however, as the presence of these markers in localized scleroderma is of dubious value. These patients have virtually no risk of systemic disease. Prognosis of skin disease is generally quite good, with lesions tending to show spontaneous regression over several years; linear morphea and generalized morphea are the exceptions, as they can be chronic and progressive. Managing and Treating Morphea In managing a patient with morphea, the most important thing you can do is reassure the patient that they will not progress to systemic sclerosis. In linear and deep types of morphea, the importance of physical therapy in preventing joint deformities and contractures cannot be overestimated. Beyond this, the treatment of morphea has been disappointing. Pruritus can be controlled with dry skin care and topical (pramoxine, menthol) or oral (antihistamines) therapy. Intralesional corticosteroids can be used on localized lesions. A small, open-label study suggested that calcipotriene (Dovonex) under occlusion can be effective.31 Recent evidence from a number of centers suggests that UVA (either broadband or UVA1) may be effective, although no controlled studies have been published.32 Rapidly progressive disease, especially in children, is often treated with high-dose corticosteroids in the presence or absence of methotrexate.33 In general, the role of immunosuppressants for this disorder is questionable. Oral calcitriol (Rocaltrol), d-penicillamine (Cuprimine), interferon gamma (Actimmune), and phenytoin (Dilantin) are probably not effective. Treating Systemic Sclerosis Systemic sclerosis (SSc) is divided into limited and diffuse forms.34 The hallmarks of both diseases are Raynaud? phenomenon (present in >95% of patients), positive ANA (>90%), and sclerosis of the hands and fingers. A mask-like facies with decreased oral aperture is sometimes a feature. The nose may appear pinched, and the lips are thin. Ridging and skin tightening of the neck is especially apparent during extension. Abnormal periungual capillary patterns are seen in >90% of patients and can help in distinguishing this disorder from morphea or non-rheumatic causes of cutaneous sclerosis. Pteryguim inversum unguis and calcinosis cutis can also be seen. The fingers can develop painful digital ulcers and pits, secondary to the vasculopathy associated with this disorder. Limited SSc (lSSc) is present in 60% of cases of SSc. Formerly termed CREST, this disorder is characterized by involvement of the forearms and hands and variable involvement on the neck and perioral region. Often, lSSc can present for many years with puffy, edematous skin without significant sclerosis. Often the first symptom is a long history of Raynaud? phenomenon. The disease can be associated with esophageal dysmotility, calcinosis and telangiectasias. Although lSSc generally has a good prognosis, these patients can suffer from isolated pulmonary hypertension in the absence of pulmonary fibrosis. This occurs in 10% to 15% of patients. These patients will rarely (5%) suffer from renal disease. Diffuse SSc (dSSc) can be diagnosed with truncal or proximal limb involvement. These patients are at higher risk for pulmonary fibrosis (70%) and pulmonary hypertension (40%). Renal disease (manifested as proteinuria, azotemia, mild hypertension or renal insufficiency) occurs in 10% to 40% of patients, with patients experiencing so-called ?enal crisis?10% of the time. The latter is a medical emergency in which patients present with hypertension and hemolytic anemia. Gastrointestinal involvement can occur at any level of the GI tract, resulting in reflux, dysphagia, so-called watermelon stomach, malabsorption, diarrhea and constipation. Patients can also have pericardial effusions, conduction defects, and cardiac ischemia. Weakness (even with mild elevation of muscle enzymes) and arthralgias can also be seen. Much progress has been made in attempting to correlate autoantibody profiles with prognosis in patients with SSc. For patients with lSSc, anti-centromere antibodies (present in 40%) tend to correlate with calcinosis and vasculopathy (represented by telangiectasias and digital ischemic loss), but in general are associated with a good prognosis. lSSc patients with anti-Th/To (RNAse P) tend to have the odd finding of pulmonary fibrosis and may represent the small subset at risk for renal crisis. The PM-Scl (PM-1) antibody is found in the rare subset of lSSc patients with a myositis overlap. Patients with dSSc will have a positive autoantibody (anti Scl70, anti-fibrillarin, or anti-RNA polymerase I,II,III) 80% of the time. In the dSSc patients, Scl70 (30%) correlates with pulmonary fibrosis and cardiac involvement; anti-fibrillarin (6% to 10%) can be found in patients at risk for isolated pulmonary hypertension; anti-RNA polymerase I, II, III (40%) is associated with rapidly progressive skin disease and renal disease and thus has a poor prognosis. Thus, a careful clinical examination and proper use of autoantibody profiling can help you diagnos lSSc or dSSc, and can also help you determine which patients are at risk for certain systemic problems. ACE-inhibitors have dramatically im-proved the survival of patients with renal crisis, and now cardiopulmonary disease continues to be the leading cause of mortality in this population. In general, patients with lSSc should have quarterly blood pressure monitoring and annual pulmonary function tests, in addition to a complete review of systems. Patients at high risk of developing pulmonary hypertension (isolated decrease in DLCO, anti-fibrillarin antibodies, cough or dyspnea) can then be effectively screened with echocardiograms. Patients with dSSc should have a home blood pressure monitor and be screened quarterly with basic chemistry panels and urinalyses. This is a multi-disciplinary approach that can involve rheumatologists, pulmonologists, nephrologists and gastroenterologists. In general, the search for a treatment for systemic sclerosis has been disappointing. The treatments for GI, renal and pulmonary complications of the disease can be effective and are reviewed elsewhere.4 However, controlled trials have not definitively supported any therapy for altering the overall course of skin disease in SSc. Management is similar to that of morphea. Treatment of calcinosis cutis is difficult, although agents such as aluminum hydroxide (Maalox, Alu-Cap), warfarin (Coumadin), colchicine (Probenecid & Colchicine) and surgical excision have been used with marginal success; the most important thing is to prevent infection of the lesions. Cyclosporine A (Gengraf, Neoral, Sandimmune), methotrexate, minocycline (Dynacin, Minocin), and thalidomide all have potential benefit. In general, immunosuppression has been disappointing, as has the use of d-penicillamine, relaxin, interferon gamma, colchicine, photopheresis, and plasmapheresis. Patient education is of critical importance in SSc. Patients should contact the Scleroderma foundation at (800) 422-1113 or www.scleroderma.org for more information about support groups and invaluable literature about the disease. Patients frustrated with current treatment options may contact the Scleroderma Clinical Trials Consortium to learn about and possibly participate in ongoing clinical trials (www.sctc-online.org). Looking Ahead Current molecular techniques, such as high-throughput gene and protein analysis, are only now revealing possible gene products involved in the pathogenesis of CTD. This knowledge, along with the advent of biologic agents that are able to specifically target secreted molecules, cell types, or intracellular signaling molecules, offers some hope for patients suffering from CTD. These agents hold out the promise that we, as dermatologists, may someday be in a position to offer not only prognostic information but a real hope for cure for this unfortunate group of patients.