 \200\234generalized. \200\235 The rash is often itchy, violaceous or erythematous, and pro gresses to \201 rm \200\234hide-bound \200\235 skin with hypo- or hyperpigmentation and subsequent atrophy. \200 The \200\234circumscribed \200\235 condition tends to resolve w ithin three to \201 ve years and treatment is often unnecessary. The acral parts are spared, the trunk a nd legs being most often involved. The \200\234generalized \200\235 form can be dis \201 guring, leading to contractures, ul ceration, and occasionally malignancy. Generalized morphea may respond to PUVA. Methotrexat e may also be effective. \200 Guttate morphea is a variant with small 10 mm diameter papu les and minimal sclerosis, resembling lichen sclerosus et atrophicus. The lesions usually local ize to the neck, shoulders, and anterior chest wall. Linear morphea describes a band-like pattern of sclerosis, often in a dermatomal distributi on. The sclerotic areas often cross over joints and are associated with soft tissue and bon e atrophy, and growth defects. Treatment is similar to generalized morphea as above. Physic al therapy and appropriate exercises may help to minimize growth defects in the childhood f orm. En coup-de-saber is linear sclerosis involving the face or scalp and associated with hemiatrophy of the face on the same side. The lesion assumes a depressed ap pearance reminiscent of a scar from a saber. Scleroderma/systemic sclerosis (SSc) \200\224diffuse skin changes \200 The changes in the skin usually proceed through three phases: early, classic, and late. In the early stage, t here may be nonpitting edema of the hands and feet, most marked in the mornings and often a ssociated with Raynaud \200\231s. The skin then becomes taut, the epidermis thins, hair gro wth ceases, and skin creases disappear and the classic changes of scleroderma become more p ronounced. The classic changes remain static for many years. The late phase may evolve at any time. Truncal and limb skin softens such that it can be di f \201 cult to know that a person ever had sclerosis. However, the hand changes rarely res olve and continue to show the ravages of \201 brosis and contractures. During this phase of the disease digital pitting scars, loss of \201 nger pad tissue, ulcers, telangiectasi a, and calcinosis can occur. CUTANEOUS FEATURES OF SCLERODERMA & THEIR TREATMENT 381 All patients with SSc will have some involvement of the face and the digits (although this involvement may be mild). SSc never involves the mid-back. Skin thickening limited to the \201 ngers is called sclerodactyly . Limited scleroderma (lcSSc) is associated with skin involvement limited to the hands and face. This form of SSc, previously known as CREST, can lead to pul monary arterial hypertension in the absence of pulmonary \201 brosis. Diffuse scleroderma (dcSSc) is associated with taut hypo- or hyperpigmented skin involvement proximal to the elbow, knee, or clavicle. In this group the re is a preponderance of visceral involvement (such as pulmonary \201 brosis and renal cr isis) in the \201 rst \201 ve years of symptoms. A practical scheme for assessing dcSSc and lcSSc by dividing the disease into early and late stages is shown in Table 13.3. Raynaud \200\231s phenomenon (Table 13.4) \200 The overall prevalence of this phenomenon is between 3 \200\22310% of the population worldwide, variation depending on climate, skin color, and racial background in particular. In SSc, Raynaud \200\231s is present in approxi mately 95% of cases. Raynaud \200\231s is more than just cold \201 ngers, which is a common complaint, and often has nothing to do with autoimmunity or vasospasm. \200 A patient with Raynaud \200\231s experiences episodic vasospasm, with the following symptoms: \200 pallor of the digits (due to ischemia), followed by \200 cyano sis (due to deoxygenation), and then \200 redness with pain and tingling (due to hyperemi a following the return of blood). All three phases do not need to be observed to make a diagnosis of Raynaud \200\231s. Conti nuous blueness/cyanosis with pain, however, is not characteristic of Raynaud \200\231s. Symptoms that might suggest secondary Raynaud \200\231s include an onset in men, patients o lder than 35 years, symptoms all year round, digital ulceration, and asymmetry. The antinuclear antibodies discussed earlier (Table 13.2) should be sought, and nailfold capillaroscopy should be performed. Pathological changes seen on capil laroscopy include nailfold capillary dilatation, hemorrhage, and dropout. Both have a high predictive power for detecting those patients likely to develop SSc. Nailfold capillaroscopy can be performed by placing a drop of immersion oil on the nailfold, and then examining the area with an ophthalmoscope set at +4 0 diopters. If immersion oil is not available, clear surgical lubricant may suf \201 ce. Conservative measures should be directed at keeping the core body temperature warm, which e ncourages vasodilatation throughout the extremities. CHAPTER 13 Systemic sclerosis and related disorders 382 Table 13.3 Characterisitc \201 ndings in early and late systemic sclerosis Diffuse cutaneous features Early (<3 years from onset of disease) Late (>3 years from onset of disease) Constitutional Fatigue, weight loss Minimal Vascular Raynaud \200\231s (often mild) Severe Raynaud \200\231s. Telangiectasia Cutaneous Rapid progression involving arms, face, and trunk Stable or some regression Musculoskeletal Arthralgia, myalgia, stiffness Flexion contractures Gastrointestinal Dysphagia and \200\230heart burn \200\231 More severe dysphagia. Midgut and anorectal disease Cardiopulmonary Myocarditis, pericarditis, lung \201 brosis Progression of established disease/Pulm. Hypertension Renal Maximum risk of scleroderma renal crisis Crisis uncommon after 4 years Limited cutaneous features Early (<10 years from onset of disease) Late (>10 years from onset of disease) Constitutional None Digital ulceration or gangrene Vascular Severe Raynaud \200\231s. Telangiectasia Stable, calcinosis Cutaneous Mild sclerosis on face Flexion contractures Musculoskeletal Occasional joint stiffness More severe symptoms common. Midgut and anorectal disease Gastrointestinal Dysphagia and heartburn Slow progressive lung \201 brosis. Pulmonary hypertension. Cardiopulmonary Rarely involved Right-sided heart failure Renal Rarely involved Rarely involved CUTANEOUS FEATURES OF SCLERODERMA & THEIR TREATMENT 383 Table 13.4 The treatment of Raynaud \200\231s phenomenon Treatment Examples Comments Nonphar- macological Hand warmers. Protective clothing Universally helpful Evening primrose oil Effective in clinical trials Fish-oil capsules Parenteral vasodilator Nifedipine or Amlodipine Hypotension is possible with all of these agents. Sildena \201 l Losartan Topical nitroglycerin High rate of discontinuation due to side effects Prostacyclin For severe attacks, digital gangrene, and prior to hand surgery Surgery Digital sympathectomy. Debridement. Amputation CHAPTER 13 Systemic sclerosis and related disorders 384 Systemic features of the disease, investigation, and treatment The gastrointestinal tract ( Table 13.5) \200 The gastrointestinal tract is probably the most commonly involved system in SSc. Over 90% of all patients with lcSSc and dcSSc develop esophageal hypomotilit y, with >50% of patients with lcSSc having serious disease. The cause of gastrointestinal dysfunction in SSc is not entirely clear. Possible contributing factors include neural dysfunction, tissue \201 brosis, and muscle atrophy. In the earliest stages of neural dysfunction most patients are asymptomatic. Prokinetic drugs such as metoclopramide (5 \200\22310 mg po BID-TID) may help some patients with esophageal hypomotility. Many patients develop re \202 ux esophagitis. Simple advice such as raising the head of th e bed, taking frequent small meals, and avoiding late night snacks, may help. Patients ofte n require high-dose proton-pump inhibitors. Small bowel disease with hypomobility can lead to weight loss and malabsorption; small inte stinal bacterial overgrowth (SIBO) may exacerbate these symptoms. SIBO can be diagnosed usi ng a lactulose breath test, and treated with two-week courses of broad spectrum antibiotics (such as cipro \202 oxacin, metronidazole, doxycycline, or amoxicillin), which can be use d as needed, on a rotating basis. Ultimately the small bowel may fail, necessitating total parenteral nutrition. Atony and hypomotility of the rectum and sigmoid colon may cause constipation and incontine nce, best managed with bulking agents, although severe cases may need limited surgery or th e use of implantable sacral stimulators. Anemia due to vascular lesions in the gastrointestinal mucosa is now widely recognized. The classic appearance in the stomach is now called gastric antrum venou s ectasia (GAVE, or watermelon stomach), and these lesions may be treated by argon laser th erapy if blood loss is signi \201 cant, although this is not curative. Pulmonary disease (Table 13.6) \200 Pulmonary disease ranks second to esophageal in frequ ency of visceral disease. With the improvements in management of renal disease, pulmonary disease is now the major cause of death in SSc. \200 The major clinical manifestations are parenchymal lung disease (interstitial lung disease, organizing pneumonia, and traction bronchiectasis) and pulmonary vascular disease (isolated pulmonary hypertension, pulmonary hypertension associ ated with interstitial lung disease, and pulmonary edema). Far less common conditions inclu de pleurisy, aspiration pneumonia, drug-induced pneumonitis, and spontaneous pneumothorax. Interstitial lung disease often develops insidiously and established \201 brosis is currently untreatable. Early diagnosis is therefore vital. The Scleroderma Lung Study (SLS) demonstrated that treatment with S Y S T E M C Table 13.5 Common gastrointestinal disorders in systemic sclerosis Site Disorder Investigation Treatment I Mouth Caries, sicca syndrome Dental radiographs Oral hygiene. Arti \201 cial saliva F E A T U R E S O F Esophagus Hypomotility Barium swallow Metoclopramide Re \202 ux High-dose proton pump inhibitors Strictures Endoscopy Dilatation Stomach Gastroparesis Metoclopramide T H E D I S E A S E Gastric ulcer Barium swallow. Endoscopy Proton-pump inhibitor Small bowel Hypomotility Barium follow-through Metoclopromide Malabsorption Hydrogen breath test Pancreatic supplements. Low-dose octreotide. Nutritional support, antibiotics , I Jejunal aspiration/biopsy If serologic evidence of celiac disease is present N V E S T G A T O N & Barium enema Stool bulking agents Stool cultures I Rectal manometry Surgery. Neurostimulator Large bowel Hypomotility I Anus Incontinence T R E A T M E N T 3 8 5 3 8 6 C H A P T E R Table 13.6 Cardiopulmonary disorders in systemic sclerosis Disease Frequency Investigation Treatment 1 3 S y s t e m i c Lung disease: Pulmonary \201 brosis Most common in dcSSc (SCL-70+) Chest radiograph, lung function tests, high-resolution chest CT scan Controversial; consider cyclophosphamide Pleurisy Uncommon Chest radiograph NSAIDs. Low-dose oral prednisolone s c l e r o s i s Bronchiectasis Rare Chest CT scan Antibiotics. Physiotherapy Pneumothorax Rare Chest radiograph Chest tube, pleurodesis Pulmonary hypertension 10 \200\22315% overall Doppler echocardiogram. Catheter studies Endothelial 1 receptor antagonists (Bosentan), Prostacyclin PDE5 inhibitors Anticoagulation . Long-term oxygen therapy a n d r e l a t e d Cardiac disease: Dysrhythmias and conduction defects Common, but rarely symptomatic ECG. 24-h ambulatory cardiac monitor Dependent on rhythm \200\224drugs, pacemaker Pericarditis 10 \200\22315% overall Echocardiogram As pleurisy, above d i s o r d e r s Myocarditis Rare Prednisone, Cyclophosphamide. Diuretics Myocardial \201 brosis 30 \200\22350% of dcSSc Controversial: consider diuretics, ACE inhibitors SYSTEMIC FEATURES OF THE DISEASE, INVESTIGATION & TREATMENT 387 oral cyclophosphamide (up to 2m/kg/day) for 12 months resulted in a 2.5% improvement in for ced vital capacity. The ongoing Scleroderma Lung Study II (SLS II) compares cyclophosphamid e to mycophenolate mofetil. The plain chest radiograph is not a sensitive test for early \201 brosis. Lung function tests can be discriminatory. The single-breath diffusion test (DLCO) is abnor mal in >70% of early cases and lung volumes are often decreased. In the case of a low DLCO and normal lung volumes, the clinician should think of pulmonary arterial hypertension (PAH ); a decline in a previously stable DLCO may be indicative of emerging PAH. High-resolution CT scanning now plays a major part in detecting and following interstitial lung disease and should be performed whenever possible. Pulmonary \201 brosis tends to be associated with dcSSc and Scl-70 antibodies, and isolat ed PAH with lcSSc and anti-centromere antibodies. Recent studies suggest a prevalence of PAH of 12 \200\22315% in SSc. Right heart catheteriz ation is the gold standard method of diagnosis, but screening using this method is not prac tical. Annual echocardiography by experienced practitioners, lung function tests (including DLCO), and clinical assessment are essential to help detect subclinical disease. Treatment of PAH associated with SSc includes prostaglandins, and inhibitors of endothelin-1 or phosphodiesterase 5 inhibitors. \200 Continuous parenteral epoprostenol, a prostacyclin, improves symptoms and pulmonary artery pressures, but not mor tality. Subcutaneous and nebulized prostacyclin are also available. \200 Bosentan (62.5 \200\223125 mg po BID), an oral endothelin receptor antagonist, improves function and is now an accepted treatment. Sildena \201 l (20 mg po TID)and tadala \201 l(40 mg po QD) inhibits phosphodiesterase type 5, and enhances relaxation of vascular smooth muscle as well as inhi biting their growth. A recent double-blind placebo-controlled study of patients with idiopa thic or connective tissue disease associated pulmonary hypertension found that sildena \201 l signi \201 cantly improves 6-minute walk times and mean pulmonary artery pressure. Cardiac disease \200 There are many cardiac manifestations including pericardial effusion , arrhythmias, and myocardial \201 brosis. Heart block has been reported, but is rare. Ma ny cases are subclinical and careful monitoring is needed. More epidemiological research is needed in this area. Renal disease \200 Renal disease has been superseded by lung disease as the main cause of death in SSc due to the impact of ACE inhibitors in the treatment of hypertensive renal crisis. It remains however a major, life-threatening complication of SSc. Both epithelial and endothelial damage occur before becoming clinically detectable. CHAPTER 13 Systemic sclerosis and related disorders 388 The most characteristic pattern of involvement is scleroderma renal crisis, which generally occurs with dcSSc within the \201 rst 5 years of disease onset. In high-risk patients th e incidence may be as high as 20%, and associated with microangiopathic hemolytic anemia, e ncephalopathy, and convulsions. Mortality may reach 10%. Patients with antibodies against R NA-polymerase III are at highest risk for scleroderma renal crisis. RNA-polymerase III anti boides are found in 25 \200\22330% of patients presenting with scleroderma renal crisis. \200 A more insidious pattern of renal involvement is also reported in which there is a slow decline in glomerular \201 ltration rate accompanied by proteinuria . This is very uncommon, but probably re \202 ects a more benign vascular and \201 broti c process. Hypertension should be treated with angiotensin-converting enzyme inhibitors (ACE-I) and calcium-channel blockers. Dialysis or renal transplant may become necessary. It is important to know that considerabl e recovery of renal function can be made after an acute crisis and that decisions involving renal transplantation should be withheld for at least 1 year. Corticosteroids are known to increase the risk of renal crisis in dcSSc. Doses >15 mg daily should be avoided. Other associated risks for hypertensive renal crisis include rapidly progressive skin disease, diffuse cutaneous disease, and the presence of antibodies to RNA polymerase III. There is no evidence that prophylactic use of ACE inhibitors reduces the risk of renal crisis. The management of scleroderma renal crisis as an acute rheumatological emergency is discuss ed in Chapter 22. Other organ involvement Table 13.7 summarizes the involvement of other organs in SSc. Malignancy It has been suggested that there is an increased incidence of all malig- nancies in SSc patients. Potential causes include immunosuppressive drug use, increased incidence of cancers in scar tissue, and oncogene over- expression. There is a close temporal relatio nship in the onset of cancer and scleroderma among patients with antibodies against RNA pol ymer- ase III, implying that malignancy may initiate a scleroderma-speci \201 c immune res ponse. SYSTEMIC FEATURES OF THE DISEASE, INVESTIGATION & TREATMENT 389 Table 13.7 Other organ involvement associated with systemic sclerosis Organ Effect Frequency 20 \200\22340% Thyroid gland Spectrum of autoimmune disease. Hypothyroidism common Liver Primary biliary cirrhosis 3% of IcSSc* Nervous system Trigeminal neuralgia 5% Carpal tunnel syndrome 3% Sensorimotor neuropathy Autonomic neuropathy Genital Cavernosal artery \201 brosis causing impotence Up to 50% Antimitochondrial antibodies found in up to 25% of patients with SSc and anticentromere ant ibodies found in 10 \200\22320% of patients with primary biliary cirrhosis. CHAPTER 13 Systemic sclerosis and related disorders 390 Anti \201 brotic and immunosuppressive therapies for systemic sclerosis \200 Apart from the speci \201 c therapies alluded to in the sections on skin and systemic disease earlier in this chapter, a number of general systemic therapies are under investigation but none h ave demonstrated marked bene \201 t. Currently, no treatment can induce complete remission of the disease. Some therapies can offer partial relief and control of end-organ damage. The evaluation of treatments is extremely dif \201 cult given the complexity, heterogeneity, and episodic na ture of the disease, as well as the paucity of patients. Both antimetabolite and alkylating immunomodulatory agents have been used, particularly in early dcSSc. The majority of these therapies are currently being evaluated in controlled trials (see Table 13.8). D-penicillamine was been widely used in the past but a single randomized controlled trial has shown no bene \201 t. Novel potential anti \201 brotic therapies may develop through understanding more about anti cytokine antibodies that block \201 broblast activation (e. g., anti-TGF B , anti-IL6), or by antagonists/gene translocations that in \202 uence pre- and post-translational modi \201 cation of collagen. Halofuginone, a type I collagen synthesis inhibitor, has shown bene \201 cial effects in treating scarring and has been used with mixed effect in bleomycin-induced scler oderma. Further work is needed to assess its use in SSc. An open label study of minocycline suggests this agent does not work. \200 Studies are cu rrently underway looking at the effect of rituximab and tocilizumab in early skin disease t hat is mainly in \202 ammatory in nature. \200 Autologous stem cell transplant has been performed in severe disease, but has a high mortality rate, and the bene \201 t may not be permanent. Its place in treatment strategies needs further research. Until de \201 nitive data are available, a reasonable approach is to treat patients with severe, active skin involvement with three to six months of oral cyclophospha mide (2mg/kg/day) followed by longer term therapy with mycophenolate mofetil (up to 1.5 g t wice daily). Patients with mild, active skin disease may be treated with mycophenolate mofe til alone. ANTIFIBROTIC AND IMMUNOSUPPRESSIVE THERAPIES FOR SSc 391 Table 13.8 Antimetabolite and alkylating immunomodulatory agents being evaluated for use in treatment of SSc Agent Comment Cyclophosphamide Ef \201 cacy from trial data on lung \201 brosis. Often given with steroids Mycophenolate Improvement in skin disease Methotrexate Used by some investigators, but controversial Antithymocyte globulin Possible bene \201 t in diffuse disease, high morbidity Pooled gammaglobulin Limited data Plasmapheresis Equivocal and anecdotal Cyclosporine Bene \201 cial on skin sclerosis Watch for renal crisis Reduce dose if on calcium-channel blockers Chlorambucil Anecdotal and control trial failed to show superiority over placebo Plasmapheresis Equivocal and anecdotal Photopheresis Limited data; mixed results CHAPTER 13 Systemic sclerosis and related disorders 392 Summary \200\224the approach to systemic sclerosis Diffuse cutaneous systemic sclerosis His tory and physical examination generally establishes the diagnosis and autoantibody pro \201 les may identify poor prognosis. The extent of visceral disease should be assessed by baseline investigations as follows: \200 Basic metabolic pro \201 le \200 Creatinine c learance and urinary protein (repeat annually) \200 Barium swallow/GI endoscopy depending on symptoms \200 Lung function tests, including DLCO (annually) \200 Electrocardiogram (annually) \200 Doppler echocardiography (with estimate of pulmonary artery pressure) (repeat annually) Chest radiograph at baseline; if lung function is abnormal, this should be replaced by a hi gh-resolution CT of the chest, repeated annually. \200 Given the paucity of patients, it is important to be aware of local or national centers of expertise and patient suitability for clinical trials. Limited cutaneous systemic sclerosis By the time of presentation physical signs are usually diagnostic. Investigations are as above and treatment is mostly symptomatic, con- centrati ng on vascular (Raynaud \200\231s and pulmonary hypertension) and GI disease, with annual r eview and appropriate testing. Prognosis \200 SSc has the highest case-speci \201 c mortality of any autoimmune rheumatic disease. Estimates of 5 years mortality in scleroderma range from 34 \200\22373%. Standardized mortality ratios have been estimated at 3 \200\2234 times expected. Logistic regression modeling suggests 3 factors \200\224proteinuria, elevated ESR, and low carbon mo noxide diffusion capacity \200\224are >80% accurate at predicting mortality >5 years. Patients with renal crisis have been estimated to have a 50% mortality, although the use of ACE inhibitors and renal replacement therapies may have reduced this. Anti-topoisomerase and anti-RNA polymerase antibodies have also been associated with SSc-related mortality. Advances in the understanding of mechanisms leading to pulmonary hypertension have led to n ew therapies that, with time, may show signi \201 cant impact in slowing disease progressi on. This page intentionally left blank