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Subj: Lupus Date: 11/8/2002 8:08:11 AM Eastern Standard Time From: kathynye@... Record: 14 Title: Systemic lupus erythematosus and lupus-like syndromes. Subject(s): SYSTEMIC lupus erythematosus -- Diagnosis Source: BMJ: British Medical Journal, 5/13/95, Vol. 310 Issue 6989,p1257, 5p, 5c, 2bw Author(s): Hay, Elaine M.; Snaith, L. Abstract: Focuses on the diagnosis of systemic lupuserythematosus. Characteristic generalized arthralgia; Mucocutaneousmanifestations; Sever fatigue; Development of diseases of major organs;Preventing lupus flares; Symptomatic and supportive treatment; Pregnancywith systemic lupus erythematosus. AN: 9510221484 ISSN: 0959-8146 Full Text Word Count: 3215 Database: Academic Search Elite Section: ABC of Rheumatology SYSTEMIC LUPUS ERYTHEMATOSUS AND LUPUS-LIKE SYNDROMES Contents Clinical presentation Arthralgia Mucocutaneous manifestations Fatigue Major organ disease Investigations Management Preventing lupus flares Symptomatic and supportive treatment Disease modifying drugs Outcome with systemic lupus erythematosus Pregnancy with systemic lupus erythematosus Antiphospholipid syndrome Subacute cutaneous lupus erythematosus Discoid lupus erythematosus Incipient lupus Neonatal lupus syndrome Drug induced lupus Overlap syndromes Classification criteria for systemic lupus erythematosus (revised1982[1]) Factors that increase probability of associated connectivetissue diseasein patients with Raynaud's phenomenon Kidney biopsy in systemic lupus erythematosus Patient support groups Treatments for systemic lupus erythematosus Corticosteroid treatment for a severe lupus flare Drugs implicated in causing lupus-like syndromes Clinical features of overlap syndromes Systemic lupus erythematosus is one of a family of interrelated andoverlapping autoimmune rheumatic disorders that includes rheumatoidarthritis, scleroderma, polymyositis, dermatomyositis, and Sjogren'ssyndrome. The disease can present as a wide variety of clinicalfeatures, reflecting the many organ systems that can be affected. Thisclinical diversity is matched serologically by a wide spectrum ofautoantibodies, which tend to cluster in relation to the clinicalpattern. Systemic lupus erythematosus is rare: a general practice with 10 000registered patients is unlikely to have more than three or four patientswith the disease at any one time. It is nine times more common in womenthan in men, and nine times more common in Afro-Caribbeans and Asiansthan in white patients. Thus, general practitioners' experience willvary greatly according the ethnic mix of their registered population. Clinical presentation Consider systemic lupus erythematosus in a young woman presenting with"seronegative rheumatoid arthritis" Because lupus is so uncommon, one difficulty is considering thepossibility in the first place, particularly if the presentation isatypical or the patient is elderly or male. Differentiating lupus fromsimilar disorders can be difficult, particularly early in the course ofthe disease, because many of the clinical features are commonnon-specific complaints. Although classification criteria for lupus arewidely accepted, they are more appropriate for classifying patients inclinical trials or epidemiological studies than for making a diagnosisin individual patients. Lupus should be considered when characteristicclinical features--most commonly arthralgia, mucocutaneousmanifestations, and fatigue--occur in combination or evolve over time. Arthralgia Generalized arthralgia, with pronounced morning stiffness but little tofind on examination, is characteristic, and pain may be considerable.Although symptoms may mimic early rheumatoid arthritis, joint swelling(synovitis) is much less noticeable. About 20% of patients will developdeformity (Jaccoud-type arthropathy) of the hands owing to tendons beingaffected. This is reversible in its early stages, but it can becomepermanent and joint instability may require surgery. Mucocutaneous manifestations A wide variety of manifestations is possible. The classic malar"butterfly" rash is the textbook presentation; it usually presentsabruptly after exposure to sunlight and lasts for several days or weeks.However, most facial rashes presenting in primary care are not caused bylupus. More common causes include acne rosacea and the parvovirus"slapped cheek" rash. Rapid hair loss can be a useful marker of active disease and can lead toalopecia. The hair will, however, regrow when the disease remits unlessthe scalp is scarred. Ulceration of the mouth or, less commonly, thenose or vagina may or may not be painful, but it is also usually selflimiting. Raynaud's phenomenon occurs in about half of patients atpresentation, but it is less common and usually milder than withscleroderma or related syndromes. Conversely, most patients who presentto their general practitioner with Raynaud's syndrome will not havesystemic lupus erythematosus. If they are positive for antinuclearantibodies they are likely to eventually develop a connective disease. Fatigue Severe fatigue in conjunction with some of the above symptoms mayreflect a flare up of the disease. Chronic fatigue, however, is almostinvariable in established systemic lupus erythematosus and may reflectunderlying depression or cardiovascular deconditioning. Major organ disease Patients greatly fear developing diseases of major organs such as thekidneys or central nervous system. Reassuringly, these do not occur inmost patients, and when they do they are usually a relatively earlyfeature. Nevertheless, they are potentially life threatening and areassociated with a poorer prognosis overall. Renal disease occurs in 20-50% of all patients at some time during theirdisease, but end stage renal failure is rare (<5%). The start of diseasemay be insidious, and patients should therefore have regular dipsticktesting of their urine for protein to facilitate early and aggressivetreatment. "Cerebral lupus" is probably overdiagnosed. For example, anxiety anddepression are common but are usually caused by psychological stressesassociated with a painful, unpredictable, chronic illness rather thanreflecting cerebral lupus. Management should focus on personal socialproblems such as isolation or marital stress. Headaches have a widevariety of possible causes. "Tension headache" can be difficult todistinguish from "lupus headache"--both may be unremitting andunresponsive to simple analgesics. The latter is extremely uncommon,however, and is usually associated with other features of activedisease. Migraine is more common in patients with lupus than in thegeneral population, particularly in patients with antiphospholipidantibodies. Cardiopulmonary disease--Pleurisy and pericarditis may be presentingfeatures, and pleuritic pain may mimic that of infection or embolism.Although lung disease is uncommon, it is difficult to treat. Investigations The erythrocyte sedimentation rate should not be relied on to dictatetreatment decisions Blood tests are useful for confirming the diagnosis of systemic lupuserythematosus and for differentiating between various subsets of thedisease but are less useful for monitoring disease activity. The mostuseful screening tests are a complete blood count, erythrocytesedimentation rate, and testing for antinuclear antibody. If the test for antinuclear antibodies is negative, systemic lupuserythematosus is extremely unlikely There is often a normochromic normocytic anaemia when the disease isactive. Leucopenia or lymphocytopenia is common and is useful fordifferentiating between systemic lupus erythematosus and rheumatoidarthritis. Thrombocytopenia is an uncommon but well recognizedcomplication of lupus. Measuring C reactive protein can be a useful testfor distinguishing between a lupus flare and infection: it usuallyremains normal in a flare, unless accompanied by serositis or synovitis,but is elevated in infection. The erythrocyte sedimentation rate will beelevated in both and occasionally remains considerably elevated when thedisease seems to be clinically quiescent. More than 95% of patients with systemic lupus erythematosus haveantinuclear antibodies. However, such antibodies may be found in otherautoimmune disorders and (in low concentration) in chronic infection andelderly people. Fewer than half of patients with lupus have antibodiesto double stranded DNA at presentation: thus it is not a good screeningtest. However, rising tires of these antibodies, particularly ifaccompanied by failing concentrations of C3 and C4, may herald the startof renal disease. C3 and C4 are insensitive diagnostically. Antibodiesto soluble cellular antigens (such as La, Ro, U1 RNP, and Jo-1) can beuseful for distinguishing between lupus subsets.[23] Antiphospholipidantibodies (such as anticardiolipin antibodies or lupus anticoagulant)identify a subset of patients at particular risk of thromboemboliccomplications or fetal loss. Management Firstly, patients need explanation and reassurance, as the liability toepisodic flare engenders insecurity and apprehension. It should beemphasized that serious complications are rare and that most patientshave a normal life expectancy. Preventing lupus flares Patients should avoid exposure to sunlight (including sunbeds), which,as well as precipitating acute or subacute skin lesions, may also causea generalized lupus flare. Sunscreens with a high protection factor(factor 15 or higher) effective against ultraviolet A and B should beapplied liberally, and long sleeved clothes and sun hats should be wornin sunny weather. Topical corticosteroid preparations are sometimeshelpful for chronic skin lesions but should be used sparingly to avoidthinning of the skin. Oral contraceptive pills containing low doses of oestrogen are probablysafe with mild lupus but should be used with caution by patients withsevere lupus since they can theoretically cause a flare. They arecontraindicated in patients with migraine, hypertension, a history ofthrombosis, or high tires of anticardiolipin antibodies.Progestogen-only oral contraceptives are safe. Intrauterine devicesshould be avoided if possible because of an increased risk of infection.The evidence for use of hormone replacement therapy is not yet clearenough to be able to give general advice: probably the best policy iscautious introduction of low dose oestrogen when the disease isquiescent with closer than usual monitoring. Differentiating between a lupus flare and infection can be difficult.Infection is an important cause of mortality in patients with systemiclupus erythematosus, particularly in those taking corticosteroids orimmunosuppressive drugs. Furthermore, intercurrent infection canprecipitate a lupus flare. Hence it is important to maintain a highindex of suspicion and regard any flu-like or feverish episode lastingmore than a day or two as infection unless proved otherwise.Sulphonamides should usually be avoided because they may cause rash orsudden profound neutropenia. Symptomatic and supportive treatment Most common symptoms of systemic lupus erythematosus can be safelytreated symptomatically. Arthralgia, headaches, and non-specific chestpains may be helped by non-steroidal anti-inflammatory drugs or simpleanalgesics. Blood pressure should be checked regularly and hypertensiontreated intensively, particularly if there is renal disease. Disease modifying drugs Corticosteroids have transformed the outlook for patients with lupus butat a considerable price: much of the increased mortality late in thecourse of the disease (due to infection, cardiovascular disease, orfracture complications) may be attributable to these drugs. Once anacute episode is under control the dose of corticosteroid should beslowly reduced; complete withdrawal is optimal, but many patients arebest managed with a small maintenance dose of perhaps 5 mg or less aday. The dose of prednisolone should not be increased for non-specificconstitutional symptoms in the absence of corroborative physical signsor abnormal laboratory results, even though this may make the patientfeel better. Few lupus complications require immediate corticosteroidtreatment--it is often best to wait and see for a day or two to avoidfrequent increases in dose for non-specific symptoms. Arthralgia insystemic lupus erythematosus responds poorly to low dose prednisoloneand usually does not warrant a high dose. Antimalarial drugs--Chloroquine phosphate (250 mg daily or alternatedays) or hydroxychloroquine (200-400mg daily) is the mainstay oftreatment for skin or joint disorders. At these doses ocularcomplications are extremely rare, but it is prudent to use the lowesteffective dose. Rheumatologists and ophthalmologists continue todisagree about the need for routine screening. Hydroxychloroquine issafer, though more expensive, than chloroquine. The total dose ofchloroquine should not exceed 300 g, but it is not clear whether thereshould be such a limit for hydroxychloroquine. Immunosuppressive drugs--Azathioprine, methotrexate, andcyclophosphamide are generally reserved for life threatening diseases ofmajor organs such as the kidneys. They should be instituted andmonitored at specialist centers, with appropriate counselling givenabout the short and long term side effects. Cyclophosphamide, whethercontinuous oral, pulse, or intravenous, is of proved benefit in treatingrenal lupus but is often associated with side effects that can be severe(such as infertility, premature menopause, or bladder cancer). Gametestorage should be offered before start of treatment when possible. Mesnashould be used to reduce the risk of bladder toxicity with intravenoustreatment, but oral mesna is not feasible for patients receivingcontinuous oral treatment. All these immunosuppressive drugs have thepotential to suppress bone marrow activity, and frequent checks ofcomplete blood count and differential white cell count are mandatory. Outcome with systemic lupus erythematosus Early studies reported that fewer than half of patients survived fiveyears after diagnosis, but this figure has steadily improved. Recentstudies report five year survival rates of 86-88% and 10 year survivalrates of 76-87%. Patients who are non-white, male, or at the extremes ofthe age range fare worst. Most patients with lupus die from causesunrelated to the disease, but deaths (such as those due to infection orischaemic heart disease) are increasingly related to treatment. Renalreplacement therapy ensures that death from renal failure is uncommon. Pregnancy with systemic lupus erythematosus There is no evidence for reduced fertility in patients with systemiclupus erythematosus, and pregnancy presents little hazard for the motherif the lupus is mild or stable. Pre-existing renal disease may, however,worsen during pregnancy, and complications such as hypertension may bemore difficult to control. Pre-eclamptic toxaemia may be difficult todistinguish from renal flare. There is an increased rate of fetal loss, particularly during the secondtrimester, in patients with high titres of antiphospholipid antibodies.Pregnancies in such women should be monitored carefully in specialistunits. Overall, there is no increased risk of fetal abnormalities, butdrug treatment during pregnancy may pose problems. Antimetabolites arecontraindicated because of teratogenesis, but low dose prednisolone,chloroquine, and azathioprine are probably safe. Antiphospholipid syndrome This may occur in patients with coexisting systemic lupus erythematosusor occur alone (primary antiphospholipid syndrome). It is characterizedby thrombosis, livedo reticularis, and sometimes thrombocytopeniatogether with the lupus anticoagulant or antiphospholipid antibodies. Subacute cutaneous lupus erythematosus Intense photosensitivity and antibodies to La and Ro are the essentialfeatures of this relatively rare syndrome. Discoid lupus erythematosus In this condition lesions are obviously discoid, systemic features arerare and mild, and autoantibodies are low in titre. Incipient lupus Some patients do not progress to very active disease, and theircondition is characterized by mild arthralgia, rashes, or serositis withweak positivity for antinuclear antibodies. Neonatal lupus syndrome A small proportion of babies born to mothers with systemic lupuserythematosus (which is often mild and may even have been unrecognized)develop the neonatal lupus syndrome. This syndrome appears to berestricted to babies whose mothers have antibodies to Ro (SS-A) or La(SS- antigens. A self limiting skin rash, which may be severe, is themost common presentation. Rarely, babies may have permanent heart blocksecondary to a conduction defect, which may require treatment with acardiac pacemaker. Drug induced lupus Lupus-like syndromes may occasionally be induced by some drugs. Theymostly consist of arthralgia with positivity for antinuclear antibodies,and renal disease is rare. Antibodies to DNA are rare, but antihistoneantibodies are characteristic. The syndrome usually resolves when theoffending drug is withdrawn, but antinuclear antibodies persist formonths after. Overlap syndromes It has been suggested that the only true lupus syndrome consists ofnephritis, photosensitivity, serositis, and antibodies to DNA. Whilethis might be too purist a view, it is often difficult to categorisepatients; criteria such as those for systemic lupus erythematosus[1] orthose suggested for mixed connective tissue disease[4] do not cover allsituations. Convention, however, prefers some form of categorization,and the syndromes usually termed overlap (though some prefer the termundifferentiated connective tissue disease) tend to have certaincharacteristic features. Patients also prefer their doctor to be ableattach a label to their condition that is acceptable to others andcarries some certainty with regard to prognosis and management. Prognosis is on a case by case basis, depending on the rate ofprogression and severity and nature of involvement of organ systems.Management is similar in principle to that for systemic lupuserythematosus: the pattern of involvement dictating the treatment. It isclear that mixed connective tissue disease, for example, is not a robustsyndrome; clinical expression tends to focus on a scleroderma-like,rheumatoid-like, or myositis-like syndrome, often with cardiopulmonaryfeatures dictating the outcome. PHOTO (COLOR): Jaccoud-type arthropathy; non-erosive deformity offingers owing to tendons being affected. PHOTO (COLOR): Classic malar "butterfly" rash of systemic lupuserythematosus after exposure to sunlight (reproduced with patient'spermission). PHOTO (COLOR): Parvovirus "slapped cheek" rash. PHOTO (BLACK & WHITE): Radiograph showing changes of restrictive lungdisease in patient with lupus--"shrinking lung" appearance and linearshadows. Pulmonary function tests may eventually stabilize, butpulmonary hypertension occasionally develops. PHOTO (BLACK & WHITE): Magnetic resonance image showing avascularnecrosis of hips. Avascular necrosis may affect any joint, and treatmentwith high dose corticosteroid is a particular risk factor. PHOTO (BLACK & WHITE): Severe lupus glomerulonephritis: appearanceconfirms end stage renal failure with glomerular loss. Continuedtreatment with immunosuppressive drugs and high dose corticosteroids isunlikely to achieve any improvement in function and would probablyresult only in further toxicity. (With less histological change, furtherimmunosuppression might be justified to delay need for dialysis). Classification criteria for systemic lupus erythematosus (revised1982[1]) To be classified as having systemic lupus erythematosus, patients musthave at least four of the following criteria in the course of theirdisease: * Malar rash * Discold rash* Photosensitivity * Oral ulcers* Arthritis * Serositis* Renaldisorder * Neurologicaldisorder* Haematological * Immunologicaldisorder disorder* Presence of anti-nuclear antibodiesFactors that increase probability of associated connectivetissue diseasein patients with Raynaud's phenomenon * Onset of condition in childhood or old age * Asymmetrical manifestation of symptoms * Severe disease threatening viabllity of peripheries * Associated with other symptoms such as arthralgia, fatigue,rash, etc * Associated with abnormal results of blood tests (such as raisederythrocyte sedimentation rate, anaemia, presence of antinuclearantibodies) Kidney biopsy in systemic lupus erythematosus * May not be crucial for diagnosis of lupus glomerulonephritis ifconfirmatory features are present--known active systemic lupuserythematosus, urinary sediment with protein, casts, haematuria, andnegative urine cultures * Important as a guide to management when there is doubt as to thereversibility of renal damage Patient support groups * Support groups for patients with lupus can be most helpful [orproviding reassurance and reducing a patient's sense of isolation * Further details can be obtained from: Lupus UK 51 North Street,Romford, Essex RM1 1BA Telephone (01708) 731251 The clinical diversity of systemic lupus erythematosus makes it one ofthe most difficult autoimmune rheumatic disorders to manage. Generalpractitioners play a vital role in supporting patients with lupus andcoordinating treatment, which can easily become fragmented among varioushospital specialists. Close liaison between specialists and generalpractitioners is crucial for optimal patient care Treatments for systemic lupus erythematosus Non-steroidal anti-inflammatory drugs For symptomatic relief Antimalarial drugs (chloroquine, hydroxychloroquine) For rashes,arthritis, and malaise Corticosteroids For severe flare For maintenance treatment (in lowdoses) Immunosuppressive drugs (azathioprine, methotrexate, cyclophosphamide,etc) For severe flare (in conjunction with corticosteroids) Additional treatmentsFor hypertensionFor infectionFor cerebral lupus (such as anticonvulsants)For thrombosisFor haematological disorders (such as splenectomy)Corticosteroid treatment for a severe lupus flare Continuous oral treatment Starting dose of prednisolone is usually0-75-1 mg/kg Treatment continued at same dose for 4-10 weeks dependingon clinical response Careful reduction can then be attempted Intravenous pulses Methylprednisolone 0-5-1-5 g repeated 1-3 timesSuppresses symptoms and may modify outcome, but avascular necrosisremains a risk Intramuscular or oral mini pulses Such as 100-125 mg prednisoloneacetate intramuscularly Safer and cheaper than and probably as effectiveas other methods for symptomatic relief Drugs implicated in causing lupus-like syndromes Common * Hydralazine * Procainamide * Anticonvulsants (phenytoin, hydantoins, primidone) * Isoniazid Rare Rare * Chlorpromazine * Penicillamine * actolol * Antithyroid drugs (propylthiouracil, methylthiouracil) * Methyldopa Clinical features of overlap syndromes * Raynaud's phenomenon * "Sausage" digits * Periungual vascular distortion * Hyperglobulinaemia and presence of antibodies to several solublenuclear and cytoplasmic antigens * Relative lack of cerebrosis, antibodies to DNA, and immunecomplex glomerulonephritis * Eventual outcome of cardiopulmonary disease PHOTO (COLOR): Livedo reticularis in patient with antiphospholipidsyndrome. PHOTO (COLOR): Sausage fingers of patient with mixed connective tissuedisease. 1. Tan EM, Cohen ES, Fries JF, Masi AT, McShane DJ, Rothfield NF,et al. The 1982 revised criteria for the classification of systemiclupus erythematosus. Arthritis Rheum 1982;25:1271-7. 2. Maddison PJ. Autoantibody profile. Oxford textbook ofrheumatology. Vol 1. Oxford: Oxford University Press, 1993:389-96. 3. Isenberg DA, Horsfall AC. Systemic lupus erythematosus. Oxfordtextbook of rheumatology. Vol 2. Oxford: Oxford University Press,1993:733-55. 4. Alarcon-Segovia D, Cardiel MH. Comparison between 3 diagnosticcriteria for mixed connective tissue disease: a study of 593 patients. yRheumatol 1989;16:328-34. ~~~~~~~~By Elaine M Hay, L Snaith The ABC of Rheumatology is edited by L Snaith. Elaine M Hay is senior lecturer in community rheumatology at theStaffordshire Rheumatology Centre, Stoke on Trent, and L Snaithis senior lecturer in rheumatology at the Institute for Bone and JointMedicine, University of Sheffield Medical School. _____ Copyright of British Medical Journal is the property of BMJ PublishingGroup and its content may not be copied or emailed to multiple sites orposted to a listserv without the copyright holder's express writtenpermission. However, users may print, download, or email articles forindividual use.Source: British Medical Journal, 5/13/95, Vol. 310 Issue 6989, p1257, 5pItem: 9510221484