|Year : 2019 | Volume
| Issue : 1 | Page : 12-17
Systemic lupus erythematosus and overlap: A clinician perspective
Sanket Shah, KG Chengappa, Vir Singh Negi
Department of Clinical Immunology, JIPMER, Pondicherry, India
|Date of Web Publication||14-Feb-2019|
Department of Clinical Immunology, JIPMER, Pondicherry - 605 006
Source of Support: None, Conflict of Interest: None
Autoimmune inflammatory rheumatic diseases, also termed as autoimmune collagen vascular diseases, as the name suggests are the group of illness arising from a combination of loss of tolerance to self-antigens and shifting of the immune system into self-destructive overdrive. These are commonly classified under six mutually exclusive diseases which include systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis, polymyositis, rheumatoid arthritis (RA), and primary Sjögren syndrome, the so-called definitive connective tissue diseases. Undifferentiated and mixed connective tissue disease and overlap syndrome have also been added to the classification. An initially undifferentiated connective tissue disease may later evolve into a differentiated connective tissue disease. Here, we define the various connective tissue diseases and elaborate more upon SLE and its overlap, including the overlap of RA (RHUPUS).
Keywords: Autoimmune inflammatory rheumatic diseases, overlap, rhupus, systemic lupus erythematosus
|How to cite this article:|
Shah S, Chengappa K G, Negi VS. Systemic lupus erythematosus and overlap: A clinician perspective. Clin Dermatol Rev 2019;3:12-7
| Introduction|| |
Autoimmune inflammatory rheumatic diseases, as the name suggests, are the group of illness arising from a combination of loss of tolerance to self-antigens and shifting of the immune system into self-destructive overdrive. The vast data on clinical spectrum and antibodies associated with various phenotypes have led to the classification of these systemic autoimmune diseases under six mutually exclusive diseases which include, (1) systemic lupus erythematosus (SLE), (2) systemic sclerosis (SSc), (3) dermatomyositis (DM), (4) polymyositis (PM), (5) rheumatoid arthritis (RA), and (6) primary Sjögren syndrome. These diseases are labeled as definitive connective tissue diseases (DCTD). However, it must be remembered that these are the classification criteria and not diagnostic criteria. Hence, the diagnosis of these diseases is still left to the expertise of the treating physician.
SLE, a prototype systemic autoimmune disease, has always been a challenge for the diagnosis and follow-up due to the heterogenicity in clinical presentation, laboratory features, and disease progression. The natural history of disease further complicates the scenario as the clinical manifestations evolve variably over the period of time.
It is often observed in clinical practice that the patients, especially in early stages or with variable clinical features and positive autoantibody who do not satisfy the proposed classification criteria of DCTD, are labeled as undifferentiated connective tissue disease (UCTD). In a strict sense, however, a diagnosis of UCTD should not be done unless the patient is unclassifiable at least for 3 years because most of early UCTD gradually evolves to DCTD or an overlap syndrome (35%).
| Definition of Overlap and Mixed Connective Tissue Disease|| |
Overlap syndrome which by definition satisfies the classification criteria for two separate diseases differs from mixed connective tissue disorder (MCTD) which is again an evolved overlap syndrome strongly associated with anti-U1 ribonucleoprotein (RNP) antibody and incorporates the overlapping features of SLE, SSc, and PM. Several criteria to classify MCTD have been compared and one study reviewing four sets of diagnostic criteria (Sharp, Alarcon-Segovia, Kasukawa, and Kahn) concluded that those of Alarcon-Segovia and Kahn were better compared to others. The criteria utilized by Alarcon-Segovia had a sensitivity and specificity of 63% and 86%, respectively. It has also been reported that a DCTD evolves to the other DCTD over time. SLE overlap syndromes are reported in literature with case reports, case series, and retrospective observational studies mentioning overlap of SLE with SSc, antiphospholipid antibody syndrome, Sjögren syndrome, inflammatory myositis and also with the organ-specific autoimmune diseases such as autoimmune hepatitis and autoimmune thyroid disease. The majority of the published studies mentioning epidemiological and clinical profile of the disease or clinical trials for various treatment options are disease-centric and the subset of SLE with overlap syndromes are either excluded at the inclusion point or do not get specific mention at the analysis level. The data on the subset of SLE-associated overlap syndrome are scarce and the epidemiological studies and clinical trials are unmet need in the field of overlap syndromes. Here, we review three complex overlap syndromes associated with SLE: (1) SLE with RA, (2) SLE with inflammatory myositis, and (3) SLE with SSc.
| Epidemiology|| |
The reported overlap of a second autoimmune disease in case of SLE ranges from 17% to 38% in studies comparing the characteristics of SLE overlap syndrome to pure lupus. Rhupus, an overlap syndrome of RA and SLE, has been reported in the range of 0.01% to 2% of the total SLE cases in case series and retrospective studies. In majority of cases (83%) of rhupus syndrome, the diagnosis of RA predates the diagnosis SLE with median duration of 7.8 years, and in the remaining cases SLE either precedes RA with median duration 6.5 years or manifests simultaneously with RA. The second overlap of SSc with SLE, although seen commonly in clinical practice, lacks robust evidence in the literature and the reports are limited to case reports and few case series. The prevalence of SLE-SSc overlap in SSc cohort was reported to be 6.8% and was reported more common in the East Asian and South Asian population compared to the Western population. The third overlap of the interest of inflammatory myositis with SLE is reported in 4%–16% cases. In the largest published series of this phenotype, the occurrence of SLE was followed by average of 14.3 months for the development of myositis in six out of ten patients. In the remaining four patients, two developed myositis after the diagnosis of SLE at an average of 8 months and two had simultaneous occurrence of the SLE and myositis. The occurrence of overlap syndrome has been reported in pediatric age group in case reports, but meticulous studies with a cohort of large numbers of patients to substantiate the comparison to adult is sparse in literature. A study published from India in 2013 mentions 6 pediatric cases of overlap syndromes, with mention of cutaneous scleroderma with juvenile arthritis and SLE as well as the overlap of SLE and myositis.
| Clinical Presentation|| |
The clinical presentation of SLE is usually characterized by clinical manifestations of malar rash, alopecia, and oral ulcers as telltale sign [Figure 1]. SLE is a multisystem disease which can possibly involve any organ of the body and is associated with an array of antibodies against multiple self-cellular antigens including the double-stranded DNA (60%), Smith antigen (20%–30%), histones (70%), ribosomal P, Ro (30%), La (20%), and various others. The clinical manifestation of SLE varies both between individuals and in the same individual over the time. The severity of disease equally shows variation from being relatively mild manifestations (cutaneous and arthralgia) to a rapidly progressive life-threatening disease (rapidly progressive renal failure and diffuse alveolar hemorrhage). Classically described as the disease of female of reproductive age, the disease is not uncommon in males and children. The involvement of various system by lupus with their usual manifestations has been described in [Table 1].
| Clinical Features of Individual Overlap Syndrome|| |
Arthralgia and arthritis in patients with SLE are reported as one of the most common manifestations with prevalence up to 90% cases; up to 34% patients of SLE have arthritis at the onset of the disease. Three variants of arthritis have been described in lupus: (1) nonerosive polyarthritis involving peripheral small and large joints; (2) Jaccoud's arthropathy: a form of tendinitis that results in nonerosive arthritis with correctable deformity, showing subluxation on plain X-ray without any bone erosions; and (3) severe arthritis with deformity and evidence of erosions on radiograph: rhupus. The patients with rhupus have symmetrical polyarthritis which commonly involves small joints of hands, associated with morning stiffness of 45 min or more. The presence of a rheumatoid nodule in SLE has been considered to be a risk factor for development into rhupus syndrome. Compared to SLE patients, rhupus patients show milder lupus disease activity with SLEDAI score and also the lower incidence of major organ involvement and damage. In retrospective studies, it has been observed that rhupus patients also have a lower incidence of malar rash, autoimmune hemolytic anemia, neuropsychiatric lupus, and lupus nephritis. Patients with rhupus have a higher level of C-reactive protein and erythrocyte sedimentation rate compared to isolated SLE. The radiographic changes of rhupus are those seen typically with RA in the form of symmetrical joint space narrowing, juxtaarticlular osteopenia, and marginal erosions [Figure 2]. Although asymptomatic positivity of rheumatoid factor and anticyclic citrullinated peptide antibodies (ACPA) have been reported in SLE, patients with rhupus have a higher positivity rate and higher titers of these antibodies. The presence of ACPA in SLE has been found to be associated with a 18–28-fold higher incidence in erosive-deforming arthritis., The presence of anti-ds DNA antibody and anti-Sm antibodies did not differ between rhupus and SLE. The comparison of rhupus with SLE has been summarized in [Table 2].
|Figure 2: X-ray hands anteroposterior view showing juxtaarticular osteopenia, symmetrical joint space narrowing, and erosions|
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|Table 2: Laboratory investigations in systemic lupus erythematosus and rhupus|
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Systemic lupus erythematosus/systemic sclerosis overlap (Lupoderma)
The age at the diagnosis is younger (37.9 years) in SLE/SSC overlap syndrome compared to SSc (47.9 years). Overlapping features of lupus can be associated with both limited and diffuse cutaneous subtypes of SSc; however, the former subgroup is less commonly observed. Raynaud's phenomenon is a common manifestation reported up to 63.2% cases as initial manifestation in cases of SLE/SSc overlap syndrome [Figure 3]. The clinical features less frequently noted in overlap syndromes are calcinosis cutis, telangiectasias, and diffuse skin involvement. Scleroderma renal crisis (SRC), digital tip ulcers, and interstitial lung disease (ILD) [Figure 4] have been observed in equal frequency with SLE/SSc overlap compared to SSc alone. The manifestation of pulmonary artery hypertension is reported variably in cases of overlap syndrome. Polyserositis, pancreatitis, and avascular necrosis of the bone have been described to be more common in this overlap compared to isolated SLE. The real challenge in this overlap is the patient presenting with hypertension and renal dysfunction with the differential diagnosis being lupus nephritis and scleroderma crisis. The treatment is completely different for both and treatment of SRC with high-dose steroids which is used for the management of lupus nephritis may lead to detrimental outcome. There are no differences in the prevalence of autoantibodies such as the anticentromere antibody, anti-SCl-70 antibody, and anti-dsDNA and anti-Sm antibodies in the overlap syndrome of SLE/SSc versus individual diseases. The presence of lupus coagulant and anti-cardiolipin antibody is more frequently observed in overlap syndromes. Besides these, Anti U1-RNP antibody is reported in 44% cases of overlap syndrome of SLE/SSc.
|Figure 3: Raynaud's phenomenon. Note the involvement of the thumb, which is a pointer toward secondary Raynaud's|
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|Figure 4: Interlobular septal thickening, reticular opacities, subpleural curvilinear lines, bronchiectasis over bilateral lower lobes, suggestive of interstitial lung disease|
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Systemic lupus erythematosus-myositis overlap
Although generalized myalgia has been reported in >50% cases of SLE, as mentioned inflammatory myositis is relatively rare (4%–16%) in lupus. The patients with SLE myositis overlap are reported at younger age, and the duration of the disease was inversely correlated for the occurrence of myositis in SLE, suggesting it is an early manifestation of the disease. Although both DM and PM have been reported with SLE, the former is reported more commonly. The muscle weakness is proximal, symmetrical, and involve both the upper and lower limbs. Trunk muscles are often involved in later stages of the diseases. If treated promptly, patients with myositis in SLE have been reported less likely to have pharyngeal weakness, neck flexor weakness, and involvement of respiratory muscle. Clinical manifestation of skin rash, alopecia, vasculitis, oral ulcer, and pericarditis are reported to be significantly higher in overlap of SLE with myositis compared to SLE alone. Comparing overlap syndrome with SLE alone, Raynaud's phenomenon and pulmonary involvement in the form of clinically relevant ILD are reported more with overlap syndromes. The occurrence of erosive arthritis is more commonly described in SLE/myositis overlap and the occurrence of lupus nephritis and neuropsychiatric lupus is similar in both the groups. Laboratory investigations across SLE/myositis cohorts have shown higher incidence of leukopenia and thrombocytopenia in the overlap subgroups. The myositis-associated antibody anti-RNP is the most commonly reported (80% of the patients) in overlaps of SLE with myositis. Among the myositis-specific antibody, anti-jo-1 antibody is reported in up to 30% cases. Lupus-specific antibodies like anti-Sm antibody are reported more commonly in the overlap syndromes compared to SLE alone. ANA positivity, Anti-dsDNA, and antiphospholipid antibody positivity and occurrence of hypocomplementemia do not differ between SLE and SLE/myositis overlap. Muscle biopsy findings described in case of SLE include inflammation, vasculitis, type II fiber atrophy, vessel wall thickening, vacuolar myopathy, and rarely inclusion body myositis. Patients with overlap syndrome have muscle biopsy features with predominance of muscle inflammation and necrosis.
| Management|| |
As described previously, the patients with overlap syndrome are usually excluded from the trials involving DCTD and hence the data on the management are mainly from an expert opinion or from the recommended treatment of SLE, RA, SSc, and inflammatory myositis. General guideline to treat the various manifestation of overlap syndromes are described in [Table 3].
The principal of management as standard includes counseling of patient regarding disease, available treatment options, and the pros and cons of each of these options. Along with pharmacotherapy regular physical activity and physical and occupational therapy are important part of holistic care to the patient. The line of management of rhupus patient is low-to-moderate-dose steroid with conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, and leflunomide to prevent progress of erosive arthritis. Patients who do not respond to conventional DMARD can be tried with cyclosporine or mycophenolate mofetil. Although anti-TNF agents have shown promising effect in the treatment of conventional synthetic DMARD refractory RA, there lies a theoretical risk of flare of lupus in these patients. Rituximab and abatacept have better evidence in the management of these cases.
Systemic lupus erythematosus/myositis overlap management
Management of SLE with myositis overlap does not differ from the management of inflammatory myositis and glucocorticoids remain the mainstay of treatment. Majority of patients of SLE show good response to glucocorticoids but will need an alternative DMARD in order to effectively taper off steroids. In patients with inadequate response with steroids or adverse drug reaction of steroids or persons of any other major organ involvement with SLE, an alternative immunosuppressant agent is required upfront. Methotrexate, azathioprine, cyclosporine, cyclophosphamide, and MMF are the usually preferred second-line immunosuppressants in refractory myositis with SLE.,
| Outcome|| |
The reports suggest a better prognosis in SLE overlap syndromes when compared to well-defined connective tissue disease. Lesser major organ involvement and earlier therapeutic interventions seem to be a reason for the same.
The prognosis of rhupus has been overall reported to be better than SLE, but in the long run will depend on the severity of internal organ involvement due to the lupus component. Prompt recognition and early initiation of appropriate management prevent joint damage and improve the overall outcome of the disease.
Systemic lupus erythematosus/myositis overlap
Although myositis in SLE responds well to corticosteroids, the association of pulmonary involvement leads to early mortality with increase standardized mortality ratio compared to SLE alone indicates poor prognosis with SLE/myositis overlap. The usual adverse prognostic features implicated in inflammatory myositis such as age, severity of myositis, cardiopulmonary disease, initial response to steroid, and dysphagia require consideration in determining the prognosis of patient.
Systemic lupus erythematosus/systemic sclerosis overlap
The survival analysis comparing SLE/SSc overlap with SSC demonstrated similar survival log-rank (P = 0.06). The median survival in years is similar for both the subgroups (SSC-SLE = 26.1 years vs. SSc = 22.4 years).
| Conclusion|| |
The heterogenicity of presentation and progress of SLE becomes more complex with overlap syndromes and the key solution to this complexity is regular clinical follow-up with alertness toward iatrogenic complications, comorbidities, and infections mimicking disease activity. There is a need for dedicated clinical trials in patients of overlap syndromes for better understanding of the natural history, outcome, and treatment strategy required for these syndromes.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]