Rowell’s syndrome: a rare but distinct entity in rheumatology

  1. Atanu Chandra ,
  2. Swarup Kanta Saha ,
  3. Aritra Kumar Ray and
  4. Parthasarathi Karmakar
  1. Internal Medicine, R G Kar Medical College and Hospital, Kolkata, West Bengal, India
  1. Correspondence to Dr Atanu Chandra; chandraatanu123@gmail.com

Publication history

Accepted:06 Sep 2020
First published:23 Sep 2020
Online issue publication:23 Sep 2020

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

Rowell’s syndrome is a rare disorder characterised by an association of lupus erythematosus with erythema multiforme (EM)-like skin lesions. EM as the initial clinical presentation of systemic lupus erythematosus is also atypical and even rarer. We report the case of an 18-year-old girl admitted to our hospital with fever and polyarthralgia along with multiple discrete ill-defined target lesions with crust formation over forehead, cheek, external ears, scalp, upper chest and back (predominantly over sun-exposed areas) with ulceration over hard palate. Investigations revealed pancytopaenia, a positive rheumatoid factor, positive antinuclear antibody with a speckled pattern, anti-Smith antibody and strongly positive anti-Ro. Patient was diagnosed with Rowell’s syndrome as per clinical and laboratory features. Majority of skin lesions including oral ulcerations subsided gradually after treatment with steroids and hydroxychloroquine.

Background

Rowell’s syndrome (RS) is an uncommon entity characterised by the association of lupus erythematosus (LE) with erythema multiforme (EM)-like skin lesion. Though rare, yet it is believed to be a distinct clinical entity in rheumatology. Till 2012, total 71 case reports of RS were published in the literature as per Antiga et al.1 The association between lupus and EM was described by Scholtz for the first time in 1922.2 In 1963, Professor Neville Rowell and his colleagues reported four female patients with discoid lupus erythematosus (DLE) and EM-like skin lesions (among 120 patients of DLE).3 There may be several variations in EM-like lesions regarding their morphology (flat or elevated), site (peripheral or involvement of mucosa) and similarity to other conditions (Stevens-Johnson syndrome or toxic epidermal necrolysis).1 4

RS is a rare but distinct entity in rheumatology and systemic lupus erythematosus (SLE) presenting initially as EM-like lesions is quite uncommon.

Case presentation

An 18-year-old unmarried Indian girl was admitted in our facility with a 3-week history of erythematous and itchy skin rashes over forehead followed by subsequent involvement of face, neck, scalp, external ear, upper chest, back and both the upper limbs including palm and sole along with painful ulceration in oral cavity. She also had fever for the same duration which was initially high grade, continuous with occasional chill and rigour, but later it became low grade and intermittent. The patient also complained of arthralgia involving multiple small and large joints, redness of both eyes along with recent onset alopecia. Notably, she did not have any photosensitivity, ulceration in genital area, bloody diarrhoea, Raynaud’s phenomenon or oliguria. Patient had no history of any intake of medications (like anticonvulsants, antibiotics, non-steroidal anti-inflammatory drugs and antitubercular drugs) in recent past, nor had any history of high-risk sexual behaviour. Her previous medical history was unremarkable.

On clinical examination, temperature was raised (38.2°C) with stable vitals. She had mild pallor. Multiple well-defined erythematous papules with annular target-like lesions were present over the aforementioned areas along with ulceration over hard palate (figure 1). The lesions were more confluent over upper part of her body and few of them showed crust formation. Multiple bilateral axillary and cervical lymph nodes were enlarged which were non-tender, discrete, freely mobile with a maximum dimension 1.5 cm×2 cm. There was no evidence of any organomegaly and the examination of other systems were unremarkable.

Figure 1

(A) Multiple target-like lesions over face, (B) ulceration over hard palate and (C) target lesions over both palms.

Investigations

Laboratory investigation showed evidence of pancytopaenia, mildly raised erythrocyte sedimentation rate and a normal C reactive protein. Urine examination revealed microalbuminuria in the absence of any active sediments. An infectious panel that included HIV screening, a viral hepatitis work-up and serology for herpes infection was negative. Other biochemical investigations like liver function test, urea, creatinine, creatine kinase and coagulation profile were within the normal reference range. Chest radiograph and abdominal ultrasound were non-contributory. Fine needle aspiration cytology of right cervical lymph node showed features of reactive hyperplasia. Skin biopsy and renal biopsy could not be performed as our patient did not give consent to these. Serology revealed a positive rheumatoid factor (RF), positive antinuclear antibody (ANA) with a speckled pattern, anti-Smith antibody and strongly positive anti-Ro (SS-A). Serum complements were significantly low. A summary of the results of her laboratory tests is shown in table 1.

Table 1

Summary of relevant laboratory investigations

Tests Results Normal range
ACR, albumin to creatinine ratio; ANA, antinuclear antibody; APTT, activated partial thromboplastin time; CRP, C reactive protein; DCT, direct Coomb's test; ESR, erythrocyte sedimentation rate; INR, international normalised ratio; PT, prothrombin time.
Haemoglobin 89  120-160 g/L
Leucocytes 2.9×109 4-11×109/L
Platelet count 109×109 150-450×109/L
Creatinine 96 59–104 μmol/L
ESR 40 <20 mm (first hour)
CRP 6 Up to 10 mg/L
PT 11 (INR-1) 11 s
APTT 34 30–40 s
Urine ACR 85.8 <30 μg/mg
Rheumatoid factor 46 <10.4 IU/mL
ANA Positive in 1:160 titre
3+ (Hep2 method) speckled pattern		 –
Anti-SS-A/Ro 3+ 0 Negative
(+) Borderline
+ Positive
++ Positive
+++ Strongly positive
Anti-SS-B/La Negative Do
Anti-ribosomal P 3+ Do
Anti- ribonucleoprotein(RNP)/Smith 2+ Do
Anti-nucleosome 2+ Do
Complement C3 16.8 90–180 mg/dL
Complement C4 5.9 10–40 mg/dL
DCT Negative –

Differential diagnosis

Possible differential diagnoses in this patient were postinfective EM, EM secondary to drugs, underlying malignancy and connective tissue disorder. The present case was not preceded by any evidence of respiratory tract infection and the serology for herpes infection was also negative. She had no history of intake of any medications prior to the illness.

The patient satisfied the diagnostic criteria for SLE (2019 European League Against Rheumatism/American College of Rheumatology classification criteria) by the presence of positive ANA, fever, mucocutaneous manifestations, joint involvement, leucopaenia, thrombocytopaenia, positive anti-Smith antibody and hypocomplementaemia. The diagnosis of RS was established based on the positive diagnostic criteria for SLE along with EM-like skin lesions and suggestive laboratory findings (positive ANA with speckled pattern, positive anti-SS-A and RF). Low serum complement levels in our patient, though not characteristic of RS, may signify active lupus, especially lupus nephritis (urine albumin to creatinine ratio (ACR) is elevated also suggesting possible renal involvement). However, hypocomplementaemia in active lupus may be due to the consumption of complements during inflammation or due to the inherent deficiency of one or more alleles or both.

Treatment

Initially she was managed conservatively (adequate hydration, antipyretics). Then steroid was added in the form of oral prednisolone (1 mg/kg/day). Hydroxychloroquine (200 mg once daily) was also given along with this.

Outcome and follow-up

She showed dramatic response to treatment. Most of her skin lesions and oral ulceration disappeared over the next few days (figure 2). Steroid was tapered off gradually. Presently we follow-up her monthly in our outpatient department. She is currently on low-dose prednisolone (10 mg every alternate day) and hydroxychloroquine (200 mg/day). She has significant improvement in her quality of life and no further relapse of the skin lesion. The values of complement C3 from very low (16.8 mg/dL) pretreatment level raised to 54.6 mg/dL (normal: 90–180 mg/dL) and spot urine ACR became 42 μg/mg from 85.8 μg/mg (normal: <30 μg/mg) following 4 months of therapy.

Figure 2

(A) Healed skin lesions after treatment, and (B) healed palatal and tongue ulceration following treatment.

Discussion

The original criteria of RS as proposed by Professor Neville Rowell comprised LE, EM-like lesions and immunological abnormalities like speckled pattern of ANA, saline extract of human tissue (anti-SJT) also known as anti-Ro and RF positivity.3 In view of the inconsistent features as described in the original criteria, Lee et al suggested inclusion of chilblains in the diagnostic criteria in 1995.5

Zeitouni et al redefined the diagnostic criteria for RS in 2000: major criteria were LE in any form, EM-like lesions (mucosa may or may not be involved) and ANA positivity (speckled pattern). Among minor criteria, there were presence of chilblains, RF and anti-Ro or anti-La antibody positivity. To diagnose RS, three major criteria and one minor criterion must be satisfied.6 Considering those criteria, our patient met all the major along with two minor diagnostic criteria.

Later, Torchia et al proposed latest diagnostic standards for RS after analysis of 132 new cases.4 Major criteria were chronic cutaneous LE; EM-like lesions (typical target or targetoid lesions); at least one among ANA positivity speckled pattern, anti-Ro/SS-A and anti-La/SS-B antibodies’ positivity; and negative direct immunofluorescence (DIF) on EM-like lesions. The minor criteria were absence of triggering factors (infections or medications) and typical location (acral and mucosal) of EM, and presence of at least one of the criteria for diagnosis of SLE provided by American College of Rheumatology except discoid or malar rash, photosensitivity, chilblains, oral ulcers and ANA positivity. For diagnosis of RS, all four major and at least one minor criteria are required. Our patient met three major and three minor of these newer criteria.

There have been many controversies in literature on whether RS is a real association, an overlap, a mere coincidence or a variant of cutaneous LE. Moreover, Torchia et al concluded that RS may be considered as a rare subtype in the spectrum of lupus-specific skin lesions.4 EM is usually triggered by different infectious agents (like herpes simplex virus, mycoplasma), drugs, malignancies and connective tissue diseases.7 On the other hand, subacute cutaneous lupus erythematosus (SCLE) is a specific variant of LE, in which there is presence of annular or papulosquamous lesions usually located above the waist .8 9 Genetic predisposition, immunological abnormalities, environmental factors and drugs (thiazide diuretics, calcium channel blockers, beta-blockers, ACE inhibitors, terbinafine, proton pump inhibitors, ranitidine, antiepileptics, statins, etc) are thought to be the aetiological factors in SCLE.10 Anti-Ro antibody is seen in majority of the patients with SCLE. It is often very difficult to differentiate SCLE and EM from clinical and histopathological features. The annular lesions of SCLE often resemble EM. Necrotic keratinocytes are often found in both these conditions. Though DIF generally distinguishes these lesions, but negative DIF cannot always exclude a diagnosis of LE.11 ANA positivity is seen to be the most consistent feature in RS, occurring in 88% of cases. RF was found positive in only 41% of cases.11 The immunological characteristics seen in RS often simulate than that of SCLE.12 Drug-induced RS has also been reported in literature.13 In our patient, no triggering factor behind EM-like skin lesion was found.

According to Antiga et al, RS should be taken as a variant of SCLE, as patients with SCLE have shown antibody profile almost similar to that of RS.1 A true association between DLE and EM was present only in a minority of cases which can be considered as a mere coincidence. This thesis is supported by Shteyngarts et al and they are of opinion that the coexistence of LE and EM along with similarities in the immunological features is probably coincidental.14 A report by Roustan et al considered RS as a subcategory of SCLE.15 Due to the overlapping clinical, laboratory and dermatopathological features of cutaneous LE and EM, Aygodan et al came to the conclusion that RS is a subentity of subacute LE.16

Therapeutic options for RS are not well documented till now. Because of underlying autoimmune basis, patients with RS usually respond to immunosuppressive therapy. Most of the literature show effectiveness of systemic steroids and immunomodulators like dapsone, azathioprine and hydroxychloroquine.14 17 However, response to treatment is variable with frequent relapses in between. Oral ciclosporin has also been seen to be effective in a few cases.17 18 Our patient responded well to oral steroids with hydroxychloroquine and there is no further recurrence of the skin lesions.

From these aforementioned arguments, it can be told that RS is more of a subtype of LE than a separate clinical entity. However, RS appears to be a distinct entity within the myriads of presentations of LE. So, the cases which fulfil the existing criteria of RS should be evaluated properly to assess the clinical course and streamline therapeutic options in future.

Patient’s perspective

I am elated to have my skin lesions cured. The tireless efforts of my doctors not only gave me a definite diagnosis which is manageable by medicines but also saved me from the horror of those skin lesions, which are still stigmatised in our society.

Learning points

  • Rowell’s syndrome (RS) is believed to be a rare and distinct entity. It should be suspected in all patients with lupus erythematosus (LE) with erythema multiforme-like skin lesions and characteristic immunological findings, where there is no evidence of any precipitating factor.

  • Erythema multiforme-like skin lesions may be the initial presentation of systemic lupus erythematosus.

  • There have been many controversies in literature on whether RS is a real association, an overlap, a mere coincidence or a variant of cutaneous LE. RS might still be considered as an underdiagnosed and underestimated disease.

  • Clinicians should be acquainted with this uncommon entity. Further cases must be reported so that details about the clinical course, pathophysiology, diagnostic criteria and therapeutic options can be explored in future.

Footnotes

  • Contributors SKS: Substantial contributions to conception and design, acquisition of data, analysis of data, interpretation of data, drafting the article, revising it critically for important intellectual content and final approval of the version to be published. AC: Acquisition of data, analysis of data, interpretation of data, drafting the article, revising it critically for important intellectual content and final approval of the version to be published. AKR: Substantial contributions to conception and design, drafting the article, revising it critically for important intellectual content and final approval of the version to be published. PK: Revising it critically for important intellectual content and final approval of the version to be published.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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