The multifaceted nature of lupus: a method for evaluating lupus patients
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https://www.eduzhai.net Clinical M edicine and Diagnostics 2013, 3(2): 11-17 DOI: 10.5923/j.cmd.20130302.01 The Many Faces of Lupus: An Approach to the Assessment of a Lupus Patient Melba I. Ovalle, M. D. Nova Southeastern University, Physician Assistant Program- Orlando Campus, USA Abstract One of the first steps in evaluating a patient with lupus is to recognize that there are various subtypes of lupus. Determining wh ich variant of lupus in afflicting the patient will determine the extent of disease involvement and even prognosis for the patient. Certain anti-nuclear antibodies and bio markers for lupus have been shown to correlate with disease activity. Recognizing the prognostic indicators of active lupus can help guide a clin ician in choosing the appropriate pharmacologic t reat ments for their lupus patients. This clinical rev iew and summary of the literature was derived fro m med ical and online databases such as PubMed , Cochrane review, up-to-date, the American Co llege of Rheu matology and American Co llege of Physicians Visual Diagnostic Logical Imaging resources. The following is an ev idence-based, objective and balanced summation of this literature review along with the author’s own rheumatologic clinical experience over the past 25 years. For the first time in decades, consensus guidelines have been established for the management of lupus nephritis. In addition, the first Food and Drug Administration-approved biologic agent, belimu mab, is now available for the treatment of certain manifestations of systemic lupus erythematosus. The reader will be able to recognize at the bedside the various subtypes of lupus, parameters of disease activity and the appropriate selection of treatment modalit ies. Keywords Antiphospholipid, Autoantibodies, Lupus 1. Introduction The word lupus means “wo lf” in Latin. Historically, physicians often thought the facial lesions of lupus patients resembled the bites of a wolf. The images of this disease often raised fear and frustration among patients as well as their doctors. Over the past century, the recognition and classification of various subtypes of lupus, the fractionation of auto-antibodies and their prognostic significance have facilitated the recognition and management of the various subsets of lupus. For the first time in several decades, a biologic agent approved by the U.S. Food and Drug Admin istration has been added to the treatment armamentariu m for systemic lupus erythematosus (1). 2. First Steps in the Evaluation of a Lupus Patient One of the first steps in the evaluation of a patient is to recognize wh ich population of patients is likely to succumb to a disease. Lupus is a prototypical autoimmune disease which has a female preponderance. Peak incidences occur * Corresponding author: firstname.lastname@example.org (Melba I Ovalle) Published online at https://www.eduzhai.net Copyright © 2013 Scientific & Academic Publishing. All Rights Reserved during one’s most productive years of life: 15 through 45 years of age (2). As with many diseases, Hispanics and African-A mericans are afflicted mo re often than Caucasians and with more severe disease (3). The pathogenesis of this disease has been recognized as probably being mu lti-factorial, with a genetic predisposition triggered by hormonal and environmental factors. The Major Histocompatibility Co mplex (M HC) Hu man Leucocyte Antigen (HLA) DR 2, DR 3 and B8 allelles serve as antigenic determinants, known as epitopes, contributing to the format ion of pathogenic auto-antibodies due to dysregulation of self-tolerance, apoptosis and cellular inflammat ion (4). The next step is to be alert for the environmental triggers that generally pre-date and/or accompany the disease presentation by performing a thorough review of systems. Antecedent infections, stress, hormonal therapies, sunlight and certain medications have been recognized as inciting triggers of lupus (5). You will learn in this monograph how certain triggers will lead to a specific type of lupus presentation, e.g. exposure to procainamide can lead to a drug-induced lupus (6). 3. Subtypes or Variants of Lupus There are numerous subtypes of lupus as shown in Table 1 (7). 12 M elba I. Ovalle: The M any Faces of Lupus: An Approach to the Assessment of a Lupus Patient Table 1. Subt ypes of Lupus & Lupus-Relat ed Syndromes* 1. Syst emic Lupus Eryt hemat osus (SLE) 2. Lupus Anti-coagulant (LAC) & Anti-Phospholipid Ant ibo dy (APL) 3. Neonatal Lupus 4. Drug-induced Erythematosus 5. Discoid Lupus Erythematosus (DLE) 6. Subacute Cutaneous Lupus Erythematosus (SCLE) *Von Feldt JM. Systemic lupus erythematosus. Recognizing its various presentations. Postgrad Med 1995; 97:79,83,86 passim. Although the usual constitutional symptoms such as fatigue, malaise, some weight loss and changes in appetite can be seen with all of these variants, each subtype can present with their own specific clin ical manifestations and prognostic significance. 3.1. Systemic Lupus Erythematosus (SLE) The most severe and widespread form of lupus is the systemic form, which generally involves mu ltiple organs such as the kidney, lungs, heart, brain and hematopoietic system as well as the skin and jo ints. The female: male rat io is 8:1, with a p redisposition in minority groups such as African-A mericans and Hispanics (8). The b i-modal peak incidence of 15 and 45 yrs of age is possibly due to the variation in hormones at that time (9). As mentioned earlier, genetic predisposition does exist with a 24-30% concordance among monozygotic twins, 2-5% concordance among dizygotic t wins suggesting other factors contributing to SLE other than genetics (9). The pathogenesis of SLE is highly co mplex. Predominantly, there is an up-regulation of CD4 helper cell activity with sub-optimal CD8 suppressor cell function, over-expression of B cells with proliferation of auto-antibodies, which in turn, form immune co mp lexes depositing on tissues causing cellular injury (10). SLE has a myriad of presentations ranging from mild, localized disease to severe mu lti-organ involvement abruptly or seque ntially over the course of months to even years. This poses a challenge to practitioners as SLE can be a great mimicker of many d iseases. The 1997 A merican College of Rheu matolo gy revised criteria for the classification of Systemic Lupus Erythematosus offers a list of the most typical clinical features found in this systemic form (Table 2) (11). Table 2. 1997 American College of Rheumatology Revised Criteria for the Classificat ion of Syst emic Lupus Erythemat osus* M 1. Malar Rash D 2. Discoid Rash S 3. Serositis; ;pleuritis, pericarditis O 4. Oral Ulcers: usually painless A 5. Arthritis: ;non-erosive P 6. Photosensitivity B 7. Blood disorders: lowWBC, Lymphs, Hemolytic anemia R 8. Renal Disease: proteinuria, RBC casts A 9. + ANA: high t iters of Ant i-Nuclear Ant ibody I 10. Immunologic: + Ant i-ds DNA, smith, Ant i-cardiolipin (ACL) abs N 11. Neurologic: seizure or psychosis *Hochberg, MC. ACR revised criteria for the classi fication of SLE (letter). Arthritis Rheum 1997; 40:1725 Although the criteria are often used for academic research and not as a sole diagnostic tool, it is still a helpful resource to imp lement at the bedside. Students in the med ical pro fession often use the mnemonic “MD SOAP BRAIN” to facilitate the memorization of each item. Often, the clin ical presentation is a young female who presents with a viral o r flu-type syndrome triggered by environmental factors with a photosensitive skin rash. This will often progress to internal organ involvement if there is a delay in d iagnosis. One of the most co mmon organs involved in SLE is the kidney. It has been recognized that certain auto-antibodies have a predilection for various organs leading to specific clin ical manifestations. For examp le, anti-ds DNA antibodies have a propensity to bind to the glomerulus with activation of complement causing sub-epithelial and/or sub-endothelial immune co mp lex deposition & significant renal damage (12). Lupus nephritis can be difficult to manage, but fo r the first time in several decades, members of a task force panel from the American College of Rheu matology have issued guidelines in the management of these patients (Table 3) (13). Table 3. American College of Rheumatology First-Time Guidelines for Lupus Nephritis : Biopsy All* Active disease based on urine sediment, proteinuria, Creatinine, Complement & Anti-ds DNA antibody levels. HCQ & ACEI for all pat ient s with prot einuria > 0.5 g/day. Maintain BP < 130/80. Statin therapy for patients with LDL cholesterol levels above 100 mg/dL. Pregnancy counseling for fertile women. Modification of Induction therapy for Class III/IV nephritis. Refractory Patients may need biologic agent (not FDA approved but trials are currently in place). HCQ= Hydoxychoroquine ACEI= Angiotensin Converting Enzyme Inhibitor *Hahn, B. H., McMahon, M. A., Wilkinson, A., etal. 2012. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res, : 797–808. In short, the take home message is to be aggressive and biopsy all lupus patients that present with nephritis, even if there is no significant change in creatinine clearance or urine sediment. Therefore, any urinalysis that demonstrates even a mild presence of microscopic hematuria or trace proteinuria without any significant decline in glo merular infiltrat ion or creatinine clearance should prompt a clinician to pursue a renal biopsy. In essence, these patients with early urine changes along with hypocomplementemia and elevated anti-dsdna antibodies have nephritis until p roven otherwise. The earlier a patient with lupus nephritis is identified, the more reversib le the condition and the better the prognosis. Once a renal biopsy is obtained, there are 6 distinct histologic categories of lupus nephritis as set forth by several organizat ions such as the World Health Organization (WHO), International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) (Table 4) (14). Clinical M edicine and Diagnostics 2013, 3(2): 11-17 13 Table 4. WHO & ISN/RPS Classificat ion of Lupus Nephritis* I. Minimal change- mild, good prognosis II. Mesangial- interstitium- variable prognosis III. FocalProliferative- spotty glomeruli IV. Diffuse Proliferative – aggressive V. Membranous – (basement membrane) heavy prot einuria (n eph rot ic) VI. Advanced Sclerosis- end stage WHO= World Health Organization ISN= International Society of Nephrology RPS= Renal Pathology Society *Weening JJ, D’Agati VD, Schwartz MM, et al.The classification of glomerulonephritis in systemic lupus erythematosus revisted. Kidney Int 2004; 65: 521 The consensus from these organizations is that a large number of affected glomeruli with diffuse architectural destruction will most likely lead to a negative response to therapy (15, 16). Other organ systems affected are the hematologic system, in which patients present with an array of blood disorders such as anemias, thrombocytopenias, pancytopenias, hemolytic anemias and clotting disorders; gastrointestinal involvement such as dyspepsia, autoimmune hepatitis, pancreatitis and vasculitis or ischemia of the intestine; pulmonary manifestations such as pleurisy, serositis, pneumonitis and pulmonary infarct ion (17). Although not typically affected in lupus patients, the myocardiu m may also be involved. Lib man-Sacks endocarditis (named after the scientists who discovered this sterile form of valvular abnormality) is the most characteristic cardiac manifestation in systemic lupus erythematosus. Lesions are usually clin ically silent, but when such disease does occur, cardiac failu re, endocarditis and embolic phenomena can cause severe neurologic and systemic co mplications (18). Neuropsychiatric manifestations of SLE, although not frequent, can present with a wide range of signs and symptoms. Fro m headache and mood disorders to active, focal neurologic deficits such as transverse myelitis, stroke and cognitive decline have a ll been reported (19). However, due to the difficu lty in the diagnosis of these conditions independent from a lupus disorder, only seizures and psychosis are part of the SLE criteria ment ioned earlier. Fortunately, there are b io markers that correlate with disease activity, help differentiate wh ich subtype of lupus is involved and also serve as prognostic indicators. The anti-neuronal antibodies and anti-ribosomal antibodies correlate with CNS involvement , anti-ribosomal antibodies predisposing to Mixed Connective Tissue Disease (MCTD) and Raynaud’s phenomenon,anti-SSA(Ro) and anti-SSB(La) antibodies associated with a sicca co mplex as in Sjogren’s syndrome and anti-phospholipid antibody or lupus anticoagulant associated with thrombophilia (20,21). 3.2. Lupus Anti-coagul ant and the Anti-Phos pholipi d Anti body Syndrome (LAC or APL) Contrary to its name, the lupus anticoagulant (LAC) is actually an immunoglobulin with thro mbotic properties binding to the phospholipids of cell membranes as well as plasma cell proteins such as beta 2 glycoprotein I. It is an inhibitor globulin wh ich causes an increase in activated partial thro mboplastin time when testing a patient’s serum with LA C. Th is and other anti-phospholipid (APL) antibodies cause a hypercoagulable state resulting in frequent miscarriages, arterial and venous thrombosis and thrombocytopenia (22). APL antibody can exist by itself and often these patients will have a h istory of recurrent spontaneous abortions as the sole comp laint (23). A typical rash, livedo reticu laris, is characteristic in these patients (Figure 1). Figure 1. Livedo Reticularis Up to 30 to 35% of SLE patients have these APL antibodies and, in some cases, a catastrophic form causing severe thrombotic strokes and even death have been reported (24). Most patients will be controlled with the use of a baby aspirin and/or warfarin. Aggressive anticoagulation and pulse steroids may be required fo r mo re severe cases. 3.3. Neonatal Lupus Neonatal lupus results from the vertical t ransmission of the mother’s auto-antibodies to the fetus. The SSA/Ro, sometimes SSB/ La, IGG antibodies travel across the placenta and disseminate throughout fetal t issue. Serious man ifestations can occur when these auto-antibodies bind to fetal cardiac tissue and cause congenital heart b lock with third degree heart block, bradycardia and/or myocarditis. Thrombocytopenia and leukopenia may also occur. The rash is the least worrisome clinical manifestation, which often resolves as the maternal antibodies wane fro m the infant in appro ximately 6 to 8 months (Figure 2). Treat ment applies to symptoms present (25). 14 M elba I. Ovalle: The M any Faces of Lupus: An Approach to the Assessment of a Lupus Patient Figure 2. Neonatal Lupus 3.4. Drug-i nduced Lupus Erythematosus Many patients have reactions to various medications and can even present with auto-immune co mplications. The pathogenesis of drug-induced lupus erythematosus is not well understood. However, a co mmon theory is that certain drugs act as haptens due to their oxidative metabolites, trigger the formation of auto-antibodies against histone proteins and cause clinical man ifestations from mild, localized disease (serositis, pleurit is) to a diffuse, systemic form of lupus (26). Although there are numerous med ications causing the formation of anti-histone antibodies and thus, drug- induced lupus, definitive drug causes have been identified as procainamide, minocin, hydralazine and bio logics such as etanercept (27). Treat ment is focused on removal o f the drug and supportive care until sy mptoms resolve. Steroids are rarely necessary. Fi gure 3. Discoid Lupus Erythemat osus 3.6. Subacute Cutaneous Lupus Erythematosus (SCLE) Subacute Cutaneous Lupus Erythematosus (SCLE) is another form of mucocutaneous lupus. This cutaneous form of lupus is more co mmon in Caucasian females. The papulosquamous rash tends to be annular, circular and non-scarring (Figure 4). 3.5. Discoi d Lupus Erythematosus (DLE) Mucocutaneous forms of lupus cause significant cosmetic difficult ies for patients. Most of these cutaneous forms are localized to the face, cheeks, upper arms and chest. There is tremendous variability of the rashes, ranging fro m the classic butterfly rash seen in SLE to fixed lesions which can scar and disfigure if not treated pro mpt ly as in Discoid Lupus Erythematosus (Figure 3). DLE is mostly localized to the skin and rarely generalizes or evolves to a systemic form of lupus. Diagnosis is confirmed by a skin biopsy revealing hyperkeratosis, follicu lar plugging and immune mononuclear cells at the dermal-ep idermal junction (28). The Anti-nuclear antibody (ANA) so characteristically sensitive in the detection of lupus tends to be negative in this variant. Sunscreen protection, intra-lesional steroid in jections and/or anti-malarials are the usual modalities of treat ment for DLE. Figure 4. Subacute Cutaneous Lupus Erythematosus It is easily aggravated by sunlight and most often occurs on sun-exposed surfaces of the body such as shoulders, extensor surfaces of the arms, upper chest, back and neck. Clin ical manifestations tend to be serositis and pleuritis with the absence of internal organ proble ms such as renal or cardiovascular complications. Typically, antibodies to the ribonucleoproteins SSA/Ro and SSB/La are present (29). Treat ment is usually photoprotection and anti-malarials such as hydroxychloroquine. 4. Monitoring Parameters for the Management of Lupus Clinical M edicine and Diagnostics 2013, 3(2): 11-17 15 As in most chronic diseases, a thorough history and physical examination are paramount for the management of lupus. Educating the patients about the early signs of a lupus flare can also allow fo r acute intervention and prevention of more serious disease. Flare-ups of lupus can present as worsening fatigue, lo w-grade fevers, arthralgias, myalgias and other constitutional symptoms. The butterfly rash may appear more intense and/or other rashes may become more disseminated. An antecedent infection, recent drug use or a photosensitivity react ion can often trigger these flares (5). This should prompt the practit ioner to obtain a panel o f acute phase reactants and biomarkers. The acute phase reactants such as sedimentation rate and C-reactive protein usually correlate with d isease activity. There have been some studies suggesting the high sensitivity C-reactive protein (hs-CRP) has been used as a risk assessment for card iovascular disease in lupus patients (30). Other serologic bio markers such as elevated anti-ds DNA antibodies and low complement levels such as CH50, C3 and C4 have been shown to correlate strongly with active lupus, particularly with renal disease (31). A complete b lood count, metabolic panel and urinalysis looking for involvement of target organs should also be obtained in the evaluation of a lupus patient. Further imaging and diagnostic studies are reserved for those patients for more severe co mplaints or disease state. 5. Pharmacotherapy and the Indications for Treatment of lupus The types of therapy that will be instituted for a lupus patient will depend on the degree of clinical presentation and severity of disease. Patients that have arthralgias and myalgias may be managed by non-steroidal anti-inflammato ry agents. Because lupus patients have a propensity for drug-induced reactions, judicious use of medications and weighing of the risks and benefits of such medication is paramount. It is worth noting that cases of men ingoencephalitis due to the use of ibuprofen in patients with autoimmune diseases, especially lupus, have been reported (32). Because corticosteroids have an abrupt onset of action, their role is reserved primarily for patients requiring immed iate therapy and/or control of their disease state. It is often employed as bridging therapy with a subsequent taper once disease modifying drugs have become effective in these patients. The actual mechanis ms of action of corticosteroids are complex and go beyond the scope of this monograph. Suffice to note that the general consensus is that corticosteroids’ mechanis m of action and side effects are due to the modulation of gene transcription (33). It is never appropriate for an abrupt termination of steroids, even with those patients on low steroid doses, as this may lead to an addisonian crisis due to the suppression of the adrenal glands. Long term us e of steroids is dis couraged due to their inherent side effects such as diabetes mellitus, osteoporosis, avascular necrosis, glaucoma and cushingoid features. Disease modify ing anti-rheumat ic drugs (DMARDs) are used for maintenance and long-term therapy of lupus patients. The profiles of these drugs range fro m slow-acting anti-rheu matic drugs (SAARDs) such as the anti-malarials (hydroxychloroquine), to anti-metabolites (methotrexate), to more immunosuppressive drugs (cyclophosphamide, mofet il mycophenalate). Lupus patients with rashes and non-erosive arthrit is benefit fro m the use of hydroxychloroq uine. Hydro xychloroquine is now considered the gold standard for the control of this disease due to its beneficial effects on the suppression of flares, controlling dyslipidemi as and prolongation of survival rates in lupus patients (34). Methotrexate is often used as a steroid-sparing agent and/or as a maintenance drug after induction therapy with cytotoxic agents (35). Lupus patients with more severe systemic states involving renal, neurologic and/or vasculitis are treated with cyclophosphamide, mofetil mycophenalate or azathioprine (36, 37). Fo r the first time in over half a century, a FDA-approved biologic agent, belimu mab (Ben lysta), now available for SLE patients, is a human monoclonal antibody which functions as a B-ly mphocyte stimulator (BLyS) - specific inhibitor, b locking the binding of soluble BLyS, a B-ce ll survival factor, to its receptors on B cells (1). It has long been speculated that B-cell modulation may be beneficial for lupus patients which has been the impetus for more investigational agents (38). Belimu mab was studied and approved for adult patients with act ive, autoantibody-positive SLE receiving standard therapy such as NSAIDs, steroids, anti-malarials and immunosuppressives. It is ad min istered as infusion therapy: IV 10 mg/ kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter. The trial noted the adverse effects of increased infections, nausea, diarrhea, depression and even mortality mo re than placebo (39). One of the major crit icisms of the BLISS study was the exclusion of lupus patients with kidney and CNS involvement fro m the trial. In addition, African A merican & Hispanic patients in the study were a small samp le size and did not appear to respond to treatment with belimu mab (Benlysta). The study lacked sufficient numbers to establish a definite conclusion in these particular patients. However, extension trials for this subpopulation of patients may help evaluate the safety and effectiveness of Benlysta. 6. Conclusions Lupus is a chronic inflammatory autoimmune disease which can affect any organ system, but mainly involves the skin, joints, kidneys and nervous system. The d iagnosis of lupus and the recognition of its various subtypes must be based on the proper constellation of clinical findings and laboratory evidence. Recognition of the pathogenic auto-antibodies and their targeted organs can help predict outcomes and treatment responses. Continual monitoring parameters include periodic follow-up and laboratory 16 M elba I. Ovalle: The M any Faces of Lupus: An Approach to the Assessment of a Lupus Patient testing to detect signs and symptoms of any new organ-system involvement. Overall t reat ment will depend on disease severity and organ involvement weighing the risks and benefits of each treatment modality. ACKNOWLEDGEMENTS I would like to thank Dr. Augusto Montalvo, Assistant Clin ical Professor of Dermatology, Feinberg School of Medicine, in Ch icago, Illino is for his assistance in edit ing. I also thank LogicalImages.com for assistance in obtaining these photographs. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res, 64: 797–808.  Weening JJ, D’Agati VD, Schwartz MM , et al. 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