Atypical Lupus Presentations and Their Prognostic Implications
Conditions: Systemic Lupus Erythematosus (SLE)
Sponsor: Sohag University

 
 
 
 
 
Official title : Atypical Lupus Presentations and their 
Prognostic Implications 
Date  : 7-December-2025 
NCT : is not yet available 
 

 
 
 
 
Atypical Lupus 
Presentations and their Prognostic Implications 
Protocol for thesis Submitted for partial fulfillment of requirement 
of MD degree in Physical Medicine, Rheumatology & 
Rehabilitation 
Presented by 
Yasmeen Abd EL-Fatah Mohamed Ahmed 
Assistant lecturer of Physical Medicine, Rheumatology &Rehabilitation 
Department ,Faculty of Medicine, Sohag University 
Supervised by 
Prof /Ahmed Mohamed Mahrous 
Professor of Physical medicine, Rheumatology and Rehabilitation 
Department, Faculty of Medicine, Sohag University 
Dr/Asmaa Khalifa Ahmed 
Lecturer of Physical medicine, Rheumatology and Rehabilitation 
Department, Faculty of Medicine, Sohag University 
DR/Reham Alaa Eldin Hassan 
Lecturer of Physical medicine, Rheumatology and Rehabilitation 
Department, Faculty of Medicine, Sohag University 
Sohag university 
2025 
Sohag University                                                                                
Faculty of Medicine 
Physical Medicine,Rheumatology& Rehabilitation 

 
 
• Introduction 
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that involve many 
different organs and display a variable clinical course.The prevalence of SLE varies across gender, 
race and geographic regions. SLE demonstrates a striking female predominance with a peak 
incidence of disease during the reproductive years[1]. 
The initial presentation of SLE is highly variable ranging from common mild symptoms to 
rare but severe organ involvement. Many patients first present with typical features such as 
musculoskeletal, mucocutaneous manifestations like photosensitivity or oral ulcers and 
constitutional symptoms including fatigue and fever. However a smaller subset of patients may 
initially present with atypical or raremanifestations such as neuropsychiatric symptoms, 
gastrointestinal , rare mucocutaneous, severe hematologic abnormalities, pulmonary hypertension 
or myocarditis[2]. 
Rare mucocutaneous manifestations of SLE include bullous lupus, lupus panniculitis and urticarial 
vasculitis. all occurring in a small minority of patients but often indicating more active or atypical 
disease[3]. 
Neuropsychiatric SLE (NPSLE) is a complex lupus manifestation with a broad range of symptoms 
from mild cognitive issues to severe central nervous system disease. Rarer symptoms like aseptic 
meningitis, movement disorders, myelopathy and demyelination can occur as initial presentations 
[4]. 
Chest involvement in SLE commonly includes pleuritis and pleural effusion. Less common but 
serious manifestations include pulmonary hypertension, shrinking lung syndrome, interstitial lung 
disease and alveolar hemorrhage may occur[5] . 
Cardiac involvement is common in SLE affecting the pericardium, myocardium, valves, coronary 
arteries and conduction system. Pericarditis and premature coronary artery disease are most 
frequent. while myocarditis, pulmonary hypertension and Libman–Sacks endocarditis are less 
common[6]. 

 
 
Rare gastrointestinal involvement in SLE may include severe manifestations such as lupus enteritis 
(mesenteric vasculitis), protein-losing enteropathy (PLE), intestinal pseudo-obstruction or even 
intestinal necrosis[7]. 
Ocular involvement in SLE is well recognized but rare and vision-threatening manifestations 
including retinal vasculitis, vaso-occlusive retinopathy, optic neuritis and choroidopathy may  also 
occur[8]. 
A minority of SLE patients present with severorgan-dominant disease that may not initially meet 
classification criteria making diagnosis challenging. Confirmation relies on excluding other causes 
and identifying highly specific SLE features such as SLE-specific autoantibodies or supportive 
histology. When these are absent, diagnosis is often delayed until more clinical or serological signs 
develop, which may worsen long-term outcomes[9]. 
Atypical age of SLE (late-onset SLE) is commonly defined as disease onset at or after 50 years of 
age and sometimes exhibits different clinical characteristics compared with the typical SLE 
phenotype. There is a higher proportion of male patients and a lower frequency of skin rash, renal 
involvement, neuropsychiatric manifestations, hypocomplementemiaand anti-DNA antibody 
seropositivitywhereas serositis is observed more frequently. Despite lower disease activity, it 
carries greater irreversible organ damage and a worse prognosis [10]. 
ANA has a high sensitivity, ranging from 95% to 97%, but a low specificity of 20%. High levels 
of ANA can be seen in several other disorders as well as a significant proportion of the healthy 
population; hence a positive ANA does not confirm the diagnosis of SLE but a negative ANA 
makes it less likely. Immunofluorescence assay (IF) is the gold standard test for ANA[11]. 
A small but well-documented subgroup presents with true ANA-negative SLE and diagnosis relies 
on other immunologic markers (anti-Ro/SSA, anti-Sm, low complement), histopathological 
findings and strong clinical suspicion. Thrombocytopenia, low complement, positive anti-dsDNA 
and medium-high titer aPL are the main manifestations of ANA-negative SLE [12].  
 

 
 
Atypical presentations of SLE including unusual initial symptoms, predominant organ 
involvement, late-onset disease and ANA-negative remain poorly characterized. These forms are 
often associated with delayed diagnosis and potentially worse clinical outcomes. Most existing 
studies focus on isolated rare manifestations rather than analyzing atypical SLE as a cohesive 
category. Understanding these differences is crucial and this study aims to compare atypical and 
typical SLE presentations to clarify variations in prognosis, treatment requirements and subsequent 
organ involvement. 
Aim of work: 
To compare the prognosis of atypical versus typical SLE presentations, focusing on differences in 
disease activity, organ damage accrual, frequency of flares, diagnostic delay, treatment 
requirements and organ involvement during follow-up. 
Patients and Methods:  
- Type of the study:Prospective cohort study. 
Patients: 
The study will include 400 patients diagnosed according to SLICC classification criteria  as  
systemic lupus erythematosus[13] including  3oo  patients  with typical common SLE  presentation 
and 100 patients with atypical presentation as rare manifestations,ANA negative lupus, late onset 
lupus.Patients will be collected from Rheumatology outpatient clinic – Sohag University Hospital. 
Inclusion Criteria 
▪ 
Patients diagnosed as SLE according toSLICC 2012Classification Criteria[13]  : 
A. Patients presented with typical lupus presentation: 
1. age of onset (20-50) 
2. common 
initial 
manifestations 
as 
constitutional 
manifestations,arthritis, 
mucocutaneousmanifestationslike malar rash, photosensitivity and hair falling. 

 
 
3. patients with ANA positive. 
B. Patients presented with atypical lupus presentation: 
   1.any clinical presentation not belonging to classic common SLE onset features, including but 
not limited to: 
o Neuropsychiatric onset: seizure, psychosis, aseptic meningitis, transverse 
myelitis 
o Cardiopulmonary 
onset: 
pulmonary 
hypertension, 
acute 
pneumonitis, 
myocarditis, pulmonary hemorrhage 
o Gastrointestinal onset: mesenteric vasculitis, intestinal pseudo obstruction, 
pancreatitis 
o Hematologic severe onset: isolated severe thrombocytopenia, autoimmune 
hemolytic anemia, thrombotic microangiopathy 
o Dermatologic atypical onset: bullous lupus, panniculitis, vasculitic ulcers 
o Myositis  
o Fever of unknown origin (FUO) as sole initial presentation 
o Thrombotic events 
o Generalized lymphadenopathy. 
2. Patients with dominant organ affection. 
3. patients with late onset SLE. 
4. patients with ANA negative SLE. 
C.Patients who can provide informed consent. 
Exclusion criteria: 
1. Patients whose initial symptoms are clearly attributable to infection, sepsis or another non-
SLE condition. 
2. Patients with chronic pre-existing diseases that may mimic or obscure the initial SLE 
presentation (e.g. primary epilepsy, primary pulmonary hypertension, chronic liver or GI 
disease). 

 
 
3. Patients in whom onset features cannot be reliably classified as typical or atypical due to 
mixed or unclear presentation. 
Methods of the study: 
All patients will be subjected to the following: 
Full medical history from the patients including Demographic data:(Age, sex,Disease duration, 
Time of diagnosis, Diabetes Mellitus, Hypertension), Clinical manifestations: categorize into 
typical 
(constitutional, 
mucocutaneous, 
musculoskeletal),atypical 
manifestations 
(Neuropsychiatricmanifestations,Chest,Cardiac and thrombotic event) and other manifestations 
and flare frequency throughout disease course. 
Treatment 
that 
patients 
received: 
corticosteroids, 
immunosuppressive 
therapy 
eg, 
hydroxychloroquine, cyclophosphamide,mycophenolate mofetil, cyclosporine, Biological 
therapy. 
Full general and rheumatological examination and assessment including : 
Assessment of disease activity using SLEDAI-2k score  
SLEDAI-2k is a validated and widely used global index that measures lupus activity over the 
preceding 10 days. It includes clinical and laboratory domains including neurological, 
mucocutaneous, musculoskeletal, renal, hematological, serological, and constitutional 
manifestations. The total score ranges from 0 to 105, with higher scores reflecting greater 
disease activity.[14] 
Assessment of organ damage using SDI damage index: 
The SDI measures cumulative, non-reversible damage that has been present for at least 
6months. It includes12 organ systems: ocular, neuropsychiatric, renal, pulmonary, 
cardiovascular, peripheral vascular, gastrointestinal, musculoskeletal, skin, endocrine, 
 
malignancy and diabetes. The total score ranges from0 to 47 with higher scores indicating 
greater cumulative organ damage.[15] 

 
 
Laboratory investigation: 
- 
Routine laboratory investigations (CBC, S.creatine, ALT, urine analysis, ESR, 24h urine 
protein or protein creatine ratio.) 
- 
Immunological laboratory investigations:ANA (IF) ,anti dsDNA, anti-smith ,complements 
C3,C4) 
Imaging or specific investigations related to affected systems:  
- 
CT chest, MRI brain,Abdominal ultrasound,Doppler at UL,LL,ECG,Echocardiography 
- 
Stage of lupus nephritis in case of renal affection 
Ethical consideration: 
 This research will be revised by the Scientific Ethical Committee of Sohag University 
Hospital. An Informed written consent will be taken from all patients. A brief resume will 
be described to the study participants before inclusion in the study about the aim advantages 
and any hazards of the study. 
Statistical analysis: 
• 
Statistical analysis will be performed using the Statistical Package for Social Sciences 
(IBM-SPSS), version 24 (IBM, Chicago, USA). 
• 
Data will be presented as mean, standard deviation (SD), number, and percentage. Mean 
and SD will be used for quantitative variables. 
• 
Student’s t-test will be used to compare means between two groups, while one-way 
analysis of variance (ANOVA) will be used for comparisons among more than two groups. 
The Mann–Whitney test will replace Student’s t-test for non-parametric data. 
• 
Pearson’s Chi-square test will be used to compare qualitative variables; Fisher’s exact test 
will be applied when expected frequencies indicate non-parametric distribution. 
• 
Pearson correlation will assess relationships between two quantitative variables, whereas 
Spearman correlation will be used for non-parametric data. 
• 
The level of statistical significance will be interpreted as follows: 
o P > 0.05: Not significant 
o P < 0.05: Significant 

 
 
o P < 0.001: Highly significant 
 
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1. 
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3. 
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11. 
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