Managing scleroderma Challenges in primary care

Transcription

1 This is a CME (Continuing Medical Education) article. It is presented to you in collaboration with the Middle East CME organizations. Self-test answers will be published in two months. In collaboration with Jeddah Primary Care CME unit 1 Credit hour Managing scleroderma Challenges in primary care Scleroderma is a complex and challenging connective tissue disease that may affect multiple organ systems. Most patients have a slowly progressive course and can be managed with vigilant screening, monitoring and timely intervention. Vivek Thakkar BSc(Med), MB BS, FRACP Owen A. Moore MB Bch, BAO, MSc, MRCP Dr Thakkar and Dr Moore are Rheumatologists and Clinical Research Fellows at St Vincent s Hospital, Melbourne. Wendy Stevens MB BS, FRACP Mandana Dr Stevens is a Rheumatologist and Head of Scleroderma Clinic at St Vincent s Hospital, Melbourne. Nikpour MB BS, FRACP, FRCPA, PhD Dr Nikpour is a Rheumatologist at St Vincent s Hospital, Melbourne and Senior Lecturer at The University of Melbourne, Vic. Scleroderma, also known as systemic sclerosis, is a multisystem connective tissue disease of unknown aetiology, characterised by vasculopathy and fibrosis. 1 Although best known for its characteristic skin involvement, systemic sclerosis can affect a number of internal organs, making the prompt recognition and treatment of these manifestations vital. EPIDEMIOLOGY The estimated incidence rate of scleroderma is 22.8 new cases per million per year, with a prevalence of 233 cases per million. 2,3 This equates to approximately 520 new cases of scleroderma each year, with over 5300 patients with In summary scleroderma co-managed in primary care centers. Despite the female to male preponderance of 7:1, no convincing hormonalor pregnancy-related factors have been identified. Although scleroderma can occur at all ages, the peak incidence occurs between the third and fifth decades. A higher prevalence of scleroderma has been noted among non-europeans (Africans, Asians and Caribbeans), with these patients having a higher frequency of diffuse disease and interstitial lung disease (ILD). 4 Although having a first-degree relative with scleroderma remains the strongest known risk factor for developing the Scleroderma is a multisystem disease affecting the skin and a number of internal organs. Close surveillance and timely intervention for end-organ involvement is vital. Lung complications are the leading cause of mortality in patients with scleroderma, and annual screening with doppler echocardiography and pulmonary function tests are recommended. early referral of patients with the triad of puffy fingers, Raynaud s phenomenon and positive antinuclear antibodies should be considered. 22 May 2013 Volume 30 Modern Medicine

2 Figures 1a. Typical scleroderma facies with tight and shiny skin, facial telangiectasias, beak -like nose, and microstomia. Figures 1b. Scleroderma with puffy fingers, hyper pigmentation and waxy skin. Figures 1c. Chronic scleroderma changes with sclerodactyly, contracture, digital ulceration and auto-amputation. condition, the relative risk of developing scleroderma is still low at 1.6% in affected families versus 0.026% in the general population. 5 PATHOGENESIS The pathophysiology of scleroderma is complex and incompletely understood. Scleroderma is best regarded as a complex process of microvascular damage, autoimmune dysregulation and fibrosis, triggered by as yet unidentified genetic and environmental factors. 6 Disease subsets The two main subsets of scleroderma, limited cutaneous scleroderma, and diffuse cutaneous scleroderma, are classified according to the extent and distribution of skin sclerosis or thickening (see Figures 1a to c). Each of these subsets has a different propensity for the type and extent of internal organ involvement. Limited cutaneous scleroderma Patients with limited cutaneous scleroderma have skin sclerosis distal to the elbows and knees (with or without facial involvement). These patients often have a long history of Raynaud s phenomenon before diagnosis and a late peak in mortality from pulmonary arterial hypertension (PAH), which occurs in about 10 to 15% of those affected. Patients with limited cutaneous scleroderma may develop ILD (severe in approximately 15% of patients) and usually have minimal cardiac and kidney involvement. Diffuse cutaneous scleroderma In patients with diffuse cutaneous scleroderma, the skin involvement extends more proximally to involve the upper arms, thighs and/or trunk. Patients with diffuse cutaneous scleroderma tend to have worsening of their skin thickening in the first one to three years of disease, with the skin manifestations often improving to varying degrees following this early phase. Patients with diffuse cutaneous scleroderma have a higher incidence of ILD, renal crisis, cardiac disease and large joint contractures, and tend to have a worse survival overall. PAH develops in 5 to 10% of patients with diffuse cutaneous scleroderma. Diagnosis Various classification criteria for scleroderma have progressively evolved to include patients with very early disease (see Table). 7-9 These criteria rely on clinical findings in association with the presence of scleroderma-specific antibodies. A recent consensus statement from leading international experts identified Raynaud s phenomenon, puffy fingers and positive antinuclear antibodies as indicators of a diagnosis of very early systemic sclerosis, and this triad should prompt referral of patients to a rheumatologist for assessment. 9 Approximately 80% of patients with Raynaud s phenomenon, abnormal nailfold capillaroscopy and scleroderma-specific autoantibodies developed scleroderma when followed over a nine-year period. 10 Modern Medicine Volume 30 May

3 Table. Comparison of classification criteria for established, early and very early scleroderma Major criterion Minor criterion American College of Rheumatology criteria for established scleroderma *7 Scleroderma proximal to metacarpophalangeal joints Sclerodactyly Digital pitting or pulp atrophy Bibasilar pulmonary fibrosis Early scleroderma 8 Very early scleroderma 9 Raynaud s phenomenon Abnormal capillaroscopy with scleroderma pattern Scleroderma-selective autoantibodies Raynaud s phenomenon Puffy swollen digits turning into sclerodactly Abnormal capillaroscopy with scleroderma pattern Positive anticentromere antibodies Positive antitopoisomerase-1 antibodies N/A * Presence of one major criterion or two of the three minor criteria indicates scleroderma. Objective documentation of Raynaud s phenomenon and one minor criterion, or subjective evidence of Raynaud s phenomenon and both minor criteria indicates early scleroderma. Criteria considered as having a high clinical relevance for a very early diagnosis of scleroderma. Anticentromere, antitopoisomerase I, antifibrillarin, anti-pm-scl, anti-fibrillin or anti-rna polymerase I or III in a titre of 1:100 or higher. Scleroderma-specific antibodies tend to be associated with certain disease manifestations; however, the absence of specific antibodies does not rule out a diagnosis of scleroderma. For example, although the presence of anticentromere antibodies is highly specific for limited cutaneous scleroderma, fewer than half of all patients with limited cutaneous scleroderma will have this antibody. 11 The presence of anticentromere antibody has been associated with more calcinosis, telangectasias and digital ischaemia. Similarly, when we look at the antitopoisomerase antibody (also known as anti-scl-70), only one-third of all patients with diffuse cutaneous scleroderma have this antibody. Patients with Scl-70 antibodies have an increased risk of developing ILD. Anti-RNA polymerase (I, II, III) anti bodies, which are present in about 15% of patients with scleroderma, are associated with the diffuse cutaneous scleroderma subtype and joint contractures; approximately one in five patients with this antibody will develop renal crisis. 12 DIFFERENTIAL DIAGNOSES There are a number of conditions that mimic scleroderma with skin thickening as a common feature (see the box). These diseases are rare and differentiated from scleroderma by the pattern of skin thickening, extradermal organ involvement and other associated features. Raynaud s phenomenon and positive antinuclear antibodies are not features of these rare disorders. 13 SPECIFIC DISEASE MANIFESTATIONS AND MANAGEMENT Skin The extent and pattern of skin disease determines the subset of scleroderma. In patients with early diffuse disease, especially if the rate of progression of skin thickening is rapid, survival is worse and internal organs are more frequently affected. In this group, international guide lines recommend use of methotrexate therapy. 14 Other treatments that have been used in patients with progressive diffuse skin disease include mycophenolate mofetil and cyclophosphamide, particularly in those with coexisting internal organ involvement. In patients with diffuse disease in whom the skin is softening or in those with limited disease who are unlikely to develop progressive skin involvement, therapy for skin disease may not be indicated. Telangiectasiae are commonly seen in patients with scleroderma and are due to macroscopically dilated cutaneous capillaries or venules (see Figure 1c). Facial telangiectasiae may have cosmetic and psychological consequences. The management of these is centred on topical concealment and laser treatment. Musculoskeletal Involvement of the musculoskeletal system is common in patients with scleroderma and causes much of the functional disability of the condition. Musculoskeletal symptoms are estimated to occur in up to 97% of patients at some point during the disease course. Arthritis Joint involvement is often associated with skin thickening and tightening in 24 May 2013 Volume 30 Modern Medicine

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5 Figure 2. Ulcerating digital calcinosis. patients with scleroderma. Joint contractures are common. Arthralgia is also common, although it can vary from mild, intermittent arthralgia to a symmetrical, inflammatory polyarthropathy similar to that of rheumatoid arthritis. Metho trexate and other immunosuppressives may be used in patients with significant inflammatory arthritis. Tendinopathy Tendon disease may occur in patients with scleroderma with the presence of palpable tendon friction rubs, particularly around the ankles and wrists. It is associated with poorer survival, more extensive skin disease and an increased risk of renal crisis and cardiac disease. Treatment is similar to that prescribed under the skin and arthritis sections. Myopathy Muscle involvement is common in patients with scleroderma, and myositis may occasionally occur. The myopathy of scleroderma may also be due to use of medications, such as corticosteroids, or secondary to physical deconditioning. Assessment of a patient with scleroderma and muscle weakness should include measurement of muscle enzymes and consideration of further testing with electromyography or Differential diagnoses of Scleroderma Morphea Eosinophilic fasciitis Nephrogenic systemic fibrosis Scleroedema Scleromyxoedema Diabetic cheiroarthropathy Pulmonary arterial hypertension PAH affects 10 to 15% of patients with scleroderma. It is often clinically silent in the early stages with minimal symptoms. However, exertional breathlessmuscle MRI. In some patients, muscle biopsy may be indicated. Inflammatory muscle disease may be managed with use of metho trexate, azathioprine and/or intravenous immunoglobulin. General measures include the correction of vitamin D deficiency and physical therapies to prevent deconditioning. Raynaud s phenomenon, digital ulceration and calcinosis Raynaud s phenomenon, peripheral cyanosis or pallor and pain due to digital vasospasm often predates scleroderma by many years. Raynaud s phenomenon occurs in 90% of patients with scleroderma. Treatment involves the avoidance of precipitants such as cold exposure and minimising heat loss (from the head and ears, chest, hands and feet) by staying warm and using warmers. In more persistent or severe cases, treatment with oral vasodilators is indicated. The most commonly used drugs are cal cium channel blockers, such as nifedipine, felodipine and diltiazem. If these are ineffective or not tolerated, other drugs that can be trialled include transdermal nitrates, phosphodiesterase type 5 inhi bitors (tadalafil or sildenafil) and selective serotonin reuptake inhi bi tors (fluoxetine). Occasionally, intravenous iloprost (a prostacyclin analogue) is used for more severe episodes. Digital ulceration is one of the complications of scleroderma and may cause significant morbidity due to pain and poor hand function. It is estimated that up to 30% of patients with scleroderma will develop a digi tal ulcer each year. The cause is generally a combination of poor vascular supply and trauma. General management invol ves pain relief and treatment of infection, as well as use of oral vasodilators to improve blood flow. Intravenous iloprost is often used as a rescue remedy to aid the healing of persistent ulceration. Other treatments used in severe digital ulceration include botulinum toxin injections around the affected digital vessel and digital sympathectomy. Infrequently, gangrene complicates severe Raynaud s phenomenon and digital ulceration, and digital amputation may be required (in 1.6% and 0.4% of patients, respectively, in a large scleroderma cohort over 18 months). 15 Calcinosis, the deposition of insoluble calcium salts in the tissues, occurs in about 25 to 40% of patients with scleroderma (Figure 2). Commonly affected sites include the forearms, elbows, volar aspects of the fingertips, metacarpophalangeal joints and interphalangeal joints. Surgical removal of symptomatic deposits is the mainstay of current treatment. Lung disease Pulmonary disease, inclusive of PAH and ILD, is the leading cause of mortality in patients with scleroderma, accounting for over 60% of scleroderma-related deaths. 26 May 2013 Volume 30 Modern Medicine

6 Suggested algorithm for screening patients with scleroderma for PAH and ILD Patient eligible for screening Perform standard investigations/examinations, including: assess symptoms and exercise capacity examine patient and measure extent of skin involvement measure levels of haemoglobin, ANA and ENA perform lung function tests, echo, chest x-ray and ECG If all results are normal, recommend a minimum of: annual clinical review (history, examination, blood tests, ECG, PFT, 6MWT*) echo minimum every two years, but ideally annually Any abnormal results FVC <85% or >10% annual fall in FVC spap measured by echo: >30 mmhg and <40 mmhg Moderate suspicion of PAH spap measured by echo: >40 mmhg and <50 mmhg; or DLCOc <50%, FVC >85%; or annual fall in DLCOc > 20%; or unexplained dyspnoea High suspicion of PAH spap measured by echo: >50 mmhg High probability of PAH Recommend HRCT and investigate further for ILD. Recommend a minimum of: annual clinical review (history, examination, ECG, blood tests, PFT, echo, 6MWT*) if recent onset (within last two years) of diffuse disease, consider sixmonthly PFTs Check symptoms. If none, recommend a minimum of annual clinical review (history, examination, blood tests, ECG, PFT, echo, 6MWT*) If symptoms present, consider: stress echo (depending on local expertise) and RHC repeat echo and PFT six-monthly or at least annually if RHC is not conducted Recommend the following: hrct and 6MWT consider stress echo (depending on local expertise) and RHC, especially if any symptoms repeat PFT, echo and 6MWT six-monthly if RHC is not conducted Recommend a minimum of: RHC, 6MWT, HRCT, and ventilation/ perfusion lung scan Treatment as required * Perform 6MWT if resources permit. ABBREVIATIONS: 6MWT = six-minute walk test; ANA = antinuclear antibodies; DLCOc = diffusing capacity corrected for haemoglobin; echo = echocardiogram; ECG = electrocardiogram; ENA = nucleolar autoantibodies; FVC = forced vital capacity; HRCT = high resolution CT scan of the chest; ILD = interstitial lung disease; PAH = pulmonary arterial hypertension; PFT = pulmonary function tests; RHC = right heart catheterisation; spap = systolic pulmonary artery pressure. reproduced with permission from the australian scleroderma Interest group. Modern Medicine Volume 30 May

7 Figure 3. High-resolution CT scan showing interstitial lung disease with interstitial thickening, ground glass change, honey combing and traction brochiectasis. ness, fatigue and syncope often develop as the disease progresses. Current international guidelines recommend annual echocardio graphy and pulmonary function testing. A screening algorithm has been developed by the Scleroderma Interest Group to guide clinicians in the early detection of PAH (see the flowchart). 16,17 Right heart catherisation is essential for the definitive diagnosis of PAH; the latter is defined as mean pulmonary artery pressure of more than 25 mmhg at rest, with a normal pulmo nary capillary wedge pressure. PBS guidelines enable designated pulmonary hypertension centres to prescribe PAH-specific agents to patients with PAH (see the full schedule for details). These agents include endothelin receptor antagonists (bosentan and ambrisentan), phosphodiesterase inhibitors (sildenafil and tadalafil) and prostanoids (intravenous epoprostenol and inhaled iloprost). There is a growing body of evidence suggesting that screening results in the early detection and treatment of PAH and Figure 4. Endoscopic images of gastric antral vascular ectasia ( GAVE ; also known as watermelon stomach). IMAGE COURTESY OF DR P. DE CRUZ, GASTROENTEROLOGY DEPARTMENT, ST VINCENT S HOSPITAL, MELBOURNE, VIC. improves the quality of life and survival of affected patients. 18,19 However, despite best current practice, PAH still has a 50% mortality at three years. This highlights the need for an active research agenda to investigate the role of combination therapies as well as more novel therapies. Interstitial lung disease Common symptoms of ILD include exertional dyspnoea and cough. Clinically, there may be signs of reduced breath sounds and basal inspiratory crepitations. Diagnosis is based on characteristic changes on high-resolution CT scans of the lungs (Figure 3). The appropriate screening test for ILD is lung function tests. The finding of reduced forced vital capacity (FVC) or a reduced diffusing capacity is an indication for further investigation with high-resolution CT. We have shown that a simple assessment of the extent of lung disease on high- resolution CT (where limited is less than 20% disease, extensive is more than 20% and an FVC of more than 70% denotes extensive in indeterminate scans) is predictive of poor outcome on follow up. 20 This may allow the selection of patients who require treatment, as only a pro portion of those with scleroderma ILD will experience progression of their disease. In scleroderma ILD, the only therapeutic agent with proven efficacy from double-blind, randomised trials is cyclo phospha mide. 21 Treatment with cyclophosphamide has been shown to slow the progression of ILD and improve health-related quality of life. Symptomatic treatment is available with supplemental oxygen. Rarely, lung transplantation is an option. Renal disease The major manifestation of scleroderma in the kidneys is renal crisis. This condition, characterised by new-onset, accelerated hypertension or rapidly progressive oligouric renal failure, used to be the main cause of sclerodermarelated deaths, with a 90% mortality at one year. However, with the earlier recognition of this complication and the aggressive use of angio tensin converting enzyme (ACE) inhi bitors, renal crisis is no longer a lead ing cause of death in scleroderma, account ing for less than 5% of all-cause mortality in affected patients. 22 Renal crisis occurs predominately in patients with early diffuse scleroderma of less than four years duration. Other risk factors for the development of renal crisis include the presence of anti-rnp polymerase III anti body and doses of corticosteroids greater than 15 mg/day. 23 Management of renal crisis is with ACE inhibitors and aggressive control of hyper tension. Features of poor prognosis include older age, creatinine levels above 270 µmol/l at diagnosis, male gender, congestive cardiac failure and uncontrolled hypertension by day three of treatment. 24 Cardiac disease It is estimated that 15 to 35% of patients 28 May 2013 Volume 30 Modern Medicine

8 Endometriosis There is a New Way Out of the Pain Visanne 2mg once daily demonstrated: 1, 2, 3, 4 Highly effective pain relief Significant reduction of endometriotic lesions 1 Favorable safety and tolerability profile suitable for long-term use 4 L.AE.WHC Product Name: Visanne 2 mg tablets. Composition: The active substance is dienogest. Each tablet contains 2 mg dienogest. The other ingredients are lactose monohydrate, microcrystalline cellulose, potato starch,, povidone K 25, magnesium stearate (Ph. Eur.), talc, crospovidone (Type A). Indications: Visanne is a preparation for the treatment of endometriosis (painful symptoms due to displaced tissue of the lining of the womb). Visanne contains a hormone, the progestogen dienogest. Contraindications: suffering from a blood clot (thromboembolic disorder) in your veins. This may occur, for example, in the blood vessels of the legs (deep vein thrombosis) or the lungs (pulmonary embolism), a severe arterial disease, including cardiovascular disease, such as a heart attack, stroke or heart disease which causes a reduced blood supply (angina pectoris). diabetes with blood vessel damage. Severe liver disease (and your liver function values have not returned to normal). Symptoms of liver disease may be yellowing of the skin and/or itching of the whole body. a benign or malignant liver tumour. The patient suffer or have ever suffered, or if it is suspected that the patient suffer from a malignant sex-hormone dependent tumour such as cancer of the breast or the genital organs, any unexplained vaginal bleeding, allergy (hypersensitivity) to dienogest or any of the other ingredients of Visanne. If any of these conditions appear for the first time while the patient is using Visanne, the patient should stop taking it at once and consult the doctor. Warnings and Precautions: The patient must not use hormonal contraceptives of any form (tablet, patch, intrauterine system) while taking Visanne. Visanne is NOT a contraceptive. Warnings and precautions are requested If the patient: have ever had a blood clot (venous thromboembolism) or anyone in the patient immediate family has had a blood clot at a relatively early age. have a close relative who has had breast cancer, have ever suffered from depression, have high blood pressure or develop high blood pressure while taking Visanne, develop a liver disease while taking Visanne. Symptoms may include yellowing of the skin or eyes or itching all over your body. The patient should inform the doctor also if such symptoms occurred during a previous pregnancy. have diabetes or had diabetes temporarily during previous pregnancy. have ever had chloasma (golden-brown patches on the skin, particularly of the face); if so, the patient should avoid too much exposure to the sun or ultraviolet radiation. suffer from pain in the lower abdomen while taking Visanne. While taking Visanne the chance of the patient of becoming pregnant is reduced because Visanne may affect ovulation. If the patient become pregnant while taking Visanne the patient is at a slightly increased risk of having an extrauterine pregnancy (the embryo develops outside the womb). The patient should tell the doctor before she start taking Visanne, if the patient had an extrauterine pregnancy in the past or have an impaired function of the Fallopian tubes. Visanne and serious uterine bleeding: Uterine bleeding, for example in women with a condition where the mucous membrane of the patient uterus (endometrium) grows into the muscle layer of the patient uterus, called adenomyosis uteri or benign tumours of the womb sometimes called uterine fibroids (uterine leiomyomata), may become worse with the use of Visanne. If bleeding is heavy and continuous over time, this may lead to low red blood cell levels (anemia), which may be severe in some cases. In the event of anemia, the patient should discuss with the doctor if the patient should stop taking Visanne. Visanne and changes in bleeding pattern: Most women treated with Visanne experience changes in their menstrual bleeding pattern. Visanne and venous blood clots: Some studies indicate that there may be a slight, but not statistically significant, increased risk of a blood clot in the legs (venous thromboembolism) associated with the use of preparations with progestagens like Visanne. Very rarely, blood clots may cause serious permanent disabilities or may even be fatal. The risk of a venous blood clot increases: with increasing age, overweight, if the patient or one of the patient close relatives had a blood clot in the leg (thrombosis), lung (pulmonary embolism), or other organ at a young age, if the patient must have surgery, if the patient have had a serious accident or if the patient is immobilized for a long time. It is important to tell the doctor in advance that the patient is using Visanne as the treatment may have to be stopped. The doctor will tell the patient when to start Visanne again. This is usually about two weeks after the patient is back on her feet. Visanne and arterial blood clots: There is little evidence for an association between preparations with progestagens like Visanne and an increased risk of a blood clot in, for example, the bloodvessels of the heart (heart attack) or the brain (stroke). In women with hypertension the risk of stroke may be slightly enhanced by these preparations. The risk of an arterial blood clot increases: if the patient smoke. The patient is strongly advised to stop smoking when she use Visanne, especially if the patient is older than 35 years. Overweight, if one of the patient close relatives had a heart attack or stroke at a young age, high blood pressure. The patient should stop taking Visanne and contact the doctor immediately if the patient notice possible signs of a blood clot, such as: severe pain and/or swelling in one of your legs, sudden severe pain in the chest which may reach the left arm, sudden breathlessness, sudden cough without an obvious cause, any unusual, severe or long-lasting headache or worsening of migraine, partial or complete blindness or double vision, difficulty in speaking or inability to speak, giddiness or fainting, weakness, strange feeling, or numbness in any part of the body. Visanne and cancer: It is not clear from the data currently available whether or not Visanne increases the risk of breast cancer. Breast cancer has been observed slightly more often in women taking hormones compared to those not taking hormones, but it is not known whether this is caused by the treatment. For example, it may be that more tumours are detected and detected earlier in women taking hormones because they are examined by their doctor more often. The occurrence of breast tumours becomes gradually less after stopping the hormone treatment. It is important to regularly check the patient breasts and the patient should contact the doctor if the patient feel any lump. In rare cases, benign liver tumours, and in even fewer cases malignant liver tumours have been reported in women taking hormones. The patient should contact the doctor if the patient have unusually severe stomach pain. Visanne and osteoporosis: The patient have an increased risk of getting osteoporosis (weakening of bones due to loss of bone minerals), the doctor will carefully weigh the risks and benefits of treatment with Visanne because Visanne has a moderate suppressing effect on the production of oestrogen (another type of female hormone) by the patient body. Interactions: The following may reduce the effect of Visanne: medicines used for the treatment of epilepsy (e.g. phenytoin, barbiturates, primidone, carbamazepine, oxcarbamazepine, topiramate, felbamate), tuberculosis (e.g. rifampicin), HIV infections: non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), other infections (antibiotics such as griseofulvin), the herbal remedy St. John s wort. The following may increase the levels of Visanne in your blood, and result in undesirable effects: medicines such as antifungals (e.g. ketoconazole, itraconazole, fluconazole), antibiotics (e.g. erythromycin, clarithromycin and roxithromycin), antidepressants (e.g. nefazodone, fluvoxamine, fluoxetine), antacids (e.g. cimetidine), blood pressure medication (e.g. diltiazem, verapamil), protease inhibitors for HIV infections (e.g. ritonavir, saquinavir, indinavir, or nelfinavir), grapefruit, Laboratory tests: If the patient need a blood test, the patient should tell the doctor or the laboratory staff that she is taking Visanne, because Visanne can affect the results of some tests. Pregnancy and breast-feeding: The patient should not take Visanne if the patient is pregnant or breast-feeding. Important information about some of the ingredients of Visanne: This medicine contains lactose. The patient should contact the doctor before the patient take Visanne if the patient is aware that the patient have an intolerance to certain sugars. Administration: For adults, the usual dose is 1 tablet per day. The patient can start treatment with Visanne on any day of the patient natural cycle. Adult dose is one tablet every day, preferably at the same time with some liquid as needed. When a pack is finished the next one should be started without interruption. The patient should continue to take the tablets also on days of menstrual bleeding. There is no experience with Visanne treatment >15 months in patients with endometriosis. Side effects: The patient may experience changes in bleeding pattern, such as spotting, irregular bleeding or periods may stop completely. weight gain, depressed mood, problems sleeping, nervousness, loss of interest in sex, or changed mood, headache or migraine, nausea, abdominal pain, wind, swollen tummy or vomiting, acne or hair loss, back pain, breast discomfort, ovarian cyst or hot flushes, uterine/vaginal bleeding including spotting, weakness or irritability, anemia, weight loss or increase in appetite, anxiety, depression or mood swings, imbalance in the autonomic nervous system (controls unconscious bodily functions, e.g. perspiration) or disturbed attention, dry eye, tinnitus, unspecific circulatory problems or uncommon palpitations, low blood pressure, shortness of breath, diarrhoea, constipation, abdominal discomfort, inflammation of the stomach and intestines (gastrointestinal inflammation), inflammation of the gums (gingivitis), dry skin, excessive sweating, severe itching of the whole body, male pattern hair growth (hirsutism), brittle nails, dandruff, dermatitis, abnormal hair growth, hypersensitive response to light or problems with skin pigmentation, pains in your bones, muscle spasms, pains and/or a sensation of heaviness in your arms and hands or legs and feet, urinary tract infection, vaginal thrush, dryness of the genital area, vaginal discharge, pelvic pain, atrophic inflammation of the genitals with discharge (atrophic vulvovaginitis), or a lump or lumps in the breast, swelling due to fluid retention. Date of information: January References: 1. Köhler G. et al, A dose-ranging study to determine the efficacy and safety of 1, 2, and 4 mg of Dienogest daily for endometriosis, Int.J.Gynaecol Obstet 2010; 108: Strowitzki T. et al, Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study Eur J Obstet Gynecol Reprod Biol, 151 (2010) Strowitzki T. et al, Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial Hum Reprod 2010; 25: Seitz C et al, Safety of Dienogest in the long term treatment of endometriosis: A one year open label follow up study, Fertil Steril 2009; 92: S107 (abstract). For further information, Please contact: Bayer HealthCare Pharmaceuticals Representative Office Dubai Internet City - Office Park Building Block B, 5 th Floor - P.O.Box : Dubai, UAE Phone : Fax : Web: Mail: ma.pv.me@bayer.com dienogest 2mg

9 with scleroderma will develop cardiac disease and this remains subclinical in many cases. 25 A small but significant number of deaths can be attributed to cardiac involvement. Cardiac disease arises due to a combination of impaired cardiac microcirculation and myocardial fibrosis, leading to arrhythmias and ventricular wall dysfunction. Both pericarditis and pericardial effusion are occasionally seen. Management of cardiac disease focuses on optimising systolic and dia stolic function with rhythm and rate control, control of hypertension, appropriate diuresis and ventricular remodelling therapies (e.g. ACE inhibitors). Gastrointestinal involvement Gastrointestinal involvement is frequent in patients with scleroderma, with the oeso phagus and stomach most commonly affected, followed by the anorectum and small bowel. 6 In many patients, gastro intestinal involvement is a major contributor to diminished health-related quality of life. Gastro-oesophageal disease results from a combination of oesophageal dysmotility, abnormal lower oesophageal sphincter tone and delayed gastric emptying. These factors can result in gastro-oesophageal reflux disease (GORD) of varying severity requiring proton pump inhibition, often in combination with pro kinetic agents. Uncontrolled GORD may also exacerbate ILD. Gastric antral vascular ectasia refers to mucosal capillary dilatations in the stomach, which also can occur in the small bowel (Figure 4). In a primary care setting, affected patients may present with iron-deficiency anaemia. Supportive management consists of replenishing iron stores with oral or intravenous iron infusions; packed red blood cell infusions are reserved for patients with severe sympto matic anae- mia. More definitive therapy consists of upper gastrointestinal endoscopy with laser or argon photo coagulation, which may need to be repeated at regular intervals. Small bowel involvement can include small bowel intestinal bacterial overgrowth, dysmotility and pseudoobstruction with resultant gastrointestinal symptoms (e.g. nausea, vomiting, bloating, abdominal discomfort, diarrhoea and constipation) and malnutrition. Although these problems may require specialist multi disciplinary input from a gastroenterologist, rheumatologist and dietitian, cyclical antibiotics for small bowel intestinal bacterial overgrowth (e.g. selective anti biotics such as tetracyclines, quinolones and imidazoles for the first 10 days of the month, repeated if necessary), and antiemetics and prokinetics for dysmotility can be used to alleviate the symptoms. Faecal incontinence is an under-recognised and under-reported manifestation in scleroderma, affecting up to 20% of patients, and is due to atrophy of the internal anal sphincter. 26 The management of this consists of rectal tampons, pelvic floor strengthening, surgical pro cedures to repair rectal prolapses and strengthen the pelvic floor, as well as a sacral neuromodulation. Erectile dysfunction Erectile dysfunction is common in men with scleroderma and is associated with increasing age and disease severity. As in the general population, treatment of erectile dysfunction includes addressing psychological factors; cessation of offending medications; improving physical fitness; use of phosphodiesterase inhi bitors; and consideration of vacuum or implantable devices. 27 Health-related quality of life As a multisystem disease, scleroderma has a marked impact on quality of life. A survey found fatigue, Raynaud s phenomenon, hand stiffness, joint pain and difficulty sleeping to be the most commonly reported symptoms impacting on quality of life (between 79 and 89% of respondents). 28 Conclusion Scleroderma is a complex and challenging multisystem connective tissue disease. A high clinical suspicion for the disease, along with adequate surveillance for end-organ complications may greatly improve the quality of life and survival of patients. Rapidly progressive scleroderma requires early referral of the patient and an aggressive approach to treatment. However, most patients will have a slowly progressive course and can be managed with vigilant screening, monitoring and timely intervention. References A list of references is available on request to the editorial office. Acknowledgement Dr Thakkar is funded by an NHMRC postgraduate scholarship and the Australian Scleroderma Interest Group (ASIG) Clinical Research Fellowship. Systemic sclerosis research at St Vincent s Hospital Melbourne is supported by a University of Melbourne Early Career Researcher Grant. COMPETING INTERESTS: Drs Thakkar, Moore, Stevens and Nikpour are part of Australian Sclero derma Interest Group (ASIG). Funding for research undertaken by ASIG is provided by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia and Pfizer. 30 May 2013 Volume 30 Modern Medicine

10 cme questions In collaboration with Jeddah Primary Care CME unit This is a CME test. It is presented to you in collaboration with the Middle East CME organizations. To test your knowledge fill-in this questionnaire and check yourself in two months or refer to your CME unit that might have other procedures - we will publish the answers in 2 months. Managing scleroderma: challenges in primary care Section A. Case study 1. Leanne, aged 32 years, has had Raynaud s phenomenon since her teens. She has come to see you today because of some unusual skin symptoms. When you examine Leanne, she has puffy, swollen digits. Question 1. Which two of the following statements correctly describe scleroderma? a. It is primarily a joint disease b. It is often associated with Raynaud s phenomenon c. It can affect a number of internal organs d. The kidneys are always involved Question 2. Which one of the following is the leading cause of mortality in patients with scleroderma? a. Lung complications b. Renal crises c. Cardiac disease d. Stroke Case study 1 (continued). You refer to the classification criteria for scleroderma and carry out some tests. You note that Leanne has a very early form of the condition. Question 3. Which three of the following criteria suggest that Leanne has very early scleroderma? a. Puffy swollen digits turning into sclerodactly b. Raynaud s phenomenon c. Abnormal capillaroscopy d. Digital pitting Case study 1 (continued). You educate Leanne about her condition. Question 4. Which two of the following statements are most correct in regards to management of patients with very early scleroderma? a. Specialist referral is necessary in all patients with scleroderma b. Close surveillance for end-organ involvement is vital in all patients with scleroderma c. Treatment with calcium channel blockers is always needed in patients with very early scleroderma d. An aggressive approach to treatment is vital in all patients with scleroderma Question 5. How can you facilitate regular follow up in patients with conditions such as scleroderma? Select as many answers as you think appropriate. a. Use chronic care plans b. Use recall systems c. Offer appropriate education, which may include patient leaflets ( au) or patient support organisations (www. sclerodermaaustralia.com.au) d. Other please write the strategies you use. meppo 2000 PAGES OF PRESCRIBING INFORMATION FOR OVER 1800 MAJOR DRUGS. MEPPO.COM Modern Medicine Volume 30 May

11 cme questions Section B. Question 6. Which three of the following statements about the epidemiology of scleroderma are correct? a. Patients are predominantly female b. Excess oestrogen levels play a role c. The peak incidence is between the third and fifth decades d. A first-degree relative who is affected is the strongest risk factor for developing the condition Case study 2. Andrea is a 65-year-old woman with a 10-year history of limited cutaneous scleroderma. She has had no follow up for her scleroderma for the past three years. She presents to you with a six-month history of progressive shortness of breath, limiting almost all of her activities of daily living. She is a lifelong nonsmoker. Question 7. List at least three differential diagnoses for her shortness of breath. Case study 2 (continued). Andrea is diagnosed with severe pulmonary arterial hypertension and commenced on appropriate therapy. Question 8. Which two of the following best reflect the current screening recommendations for lung complications of scleroderma, before patients become breathless? a. Clinical review every year b. Clinical review every two years c. Electrocardiography only every year d. Echocardiography and pulmonary function tests every year Case study 3. Kalee is 45 years old and was diagnosed with diffuse cutaneous scleroderma three years ago. You share her care with a rheumatologist. She is a single mother with two teenage boys. Her only medication is a proton pump inhibitor to help manage her gastro-oesophageal reflux disease. Question 9. List at least three features of diffuse cutaneous scleroderma. Case study 3 (continued). Kalee is well-informed about her condition and is an active participant in a support group. She has come to see you on this cold, winter s day because of more painful, persistent Raynaud s phenomenon associated with digital ulceration. Question 10. Which of the following options might you consider to manage Kalee s problem? Choose the single best answer. a. Advise on the avoidance of cold exposure and minimisation of heat loss by keeping warm b. Recommend oral peripheral vasodilator therapies and/or analgesia c. Carry out local wound care, which may include local dressings, debridements, swabs and antibiotics d. All of the above MODERN MEDICINE If YES, VISIT MIDDLE EAST MEPPO.COM to change your address or register to receive free of charge Modern Medicine magazine and the MEPPO drug compendium 32 May 2013 Volume 30 Modern Medicine

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