Rowell's Syndrome to ds-DNA Negative Lupus Nephritis: A Yet Unreported Progression.

Rowell's syndrome is now identified as a subtype of subacute lupus erythematosus (LE) with erythema multiforme-like skin lesions, positive serum rheumatoid factor, anti-Ro La positivity and speckled pattern of antinuclear antibodies. Here we describe a case of Rowell's syndrome in an 18-year-old female who was found to be ds-DNA negative, who later progressed to develop stage V lupus nephritis (LN) over a course of 4 months. Although extremely rare, most cases of LN are drug induced. Of only seven cases of non-drug induced LN with negative dsDNA, none had cutaneous involvement. Ours was a unique case of progression of Rowells syndrome to ds-DNA negative LN.

What was known?

The presence of erythema multiforme (EM)-like lesions in lupus patients and a characteristic pattern of immunological abnormalities have been defined as Rowell's syndrome

It is now identified as a type of subacute lupus erythematosus

EM like lesions have been reported with all subsets of lupus erythematosusr.

Introduction

In 1963, Rowell et al. described a distinctive subset of patients with lupus erythematosus (LE) consisting of erythema multiforme-like skin lesions, anti-La (SS-B)/anti-Ro (SS-A) antibodies, positive serum rheumatoid factor and a speckled pattern of antinuclear antibodies.[1] Though its progression to acute LE has been documented, progression to anti-double-stranded DNA (ds-DNA) negative lupus nephritis has not been reported till date.

Case Report

An 18-year-old female presented with fever since 1 month and rash over face and forearms since 3 weeks. The patient was apparently all right prior to 1 month, when she developed high-grade continuous fever. Two days later she developed lip lesions. Three days later she developed blisters and red lesions over face and forearms and blackish lesions over forearms. She gave no history suggestive of Raynaud's phenomenon. She did not give any history of joint pains, decreased urine output and hematuria, chest pain, dyspnea, cough or no history of spontaneous bleeding tendencies. She denied any history of drug intake prior to developing similar lesions. There was no significant past or family history.

Cutaneous examination revealed lesions over face, forearms, chest and lips. Lesions over the face are in the form of palpable purpura, scars and targetoid lesions [Figure 1a and b]. Purpuric and targetoid lesions were also seen over the arms [Figure 2a] and chest. Non-tender erythematous macules and targetoid lesions were seen over palms [Figure 2b]. Crusting erosions and edema were seen over lips [Figure 3]. Hair over the frontal area was sparse and brittle. Nail-fold capillaroscopy revealed proximal nail fold erythema, ragged cuticles, and capillary telangiectasia and nail-fold infarcts [Figure 4a–c].

Figure 1

(a) Clinical photograph showing scars and targetoid lesions over face and crusting over lower lip. (b) Clinical photograph of face showing scars and targetoid lesions on closer view

Figure 2

(a) Clinical photograph showing scars and targetoid lesions and palpable purpura over arm. (b) Clinical photograph showing non tender erythematous macules and targetoid lesions were seen over palms

Figure 3

Crusting erosions and edema were seen over lips

Figure 4

(a) Nail fold capillaroscopy showing erythema, telangiactasia, ragged cuticles and infarcts over proximal nail fold. (b) Nail fold capillaroscopy showing Nailfold infarcyt and telangiectasia. (c) Nail-fold capillaroscopy showing Nail fold infact on higher magnification

Systemic examination was normal. Differential diagnosis of erythema Multiforme and Rowell's syndrome were condsidered. Complete hemogram and urine examination were normal except for a raised ESR of 30 mm/hour. Anti-nuclear antibody was positive with a titer of 1:160 and showed a speckled pattern. Anti-ds-DNA was negative. Anti- Ro antibody was found to be negative with a titer of 11 U/ml (titer of >10 U/ml is considered positive by immunofluorescence method). Rheumatoid Factor (RF) was negative. Histopathological examination of the biopsy specimen taken from targetoid lesion over the forearm revealed orthokeratosis, focal hypergranulosis, basal cell vacuolar degeneration, lymphohistiocyic infiltrate at the dermo epidermal junction with pigment incontinence [Figure 5a and b].

Figure 5

(a) Section from targetoid lesion showing orthokeratosis, focal hypergranulosis, basal cell vacuolar degeneration, lymphohistiocyic infiltrate at the dermo epidermal junction with pigment incontinence (H and E 10X). (b) Section from targetoid lesion showing basal cell vacuolar degeneration with lymphohistiocytic infiltrate at dermoepidermal junction (H and E 40X)

A diagnosis of Rowell's syndrome was made on the basis of clinical and laboratory findings. The patient was duly started on Tablet Hydroxychloroquine 200 mg twice daily and tablet prednisolone at 30 mg which was gradually tapered was gradually tapered to 5 mg over a period of 6 months. The skin lesions subsided within a month with some post inflammatory hyper pigmentation. Steroids were stopped after 6 months and hydroxychloroquine was stopped after 1 year. Four months later, she developed recurrence of lesions on face, chest, back, arms and ears. Lichenoid papules were seen over the over face, arms, forearms and hands. Erythematous papules with dusky red hue were seen over the concha of ears and forearms. Twenty-four hour urine protein examination revealed 472 grams of protein per 24 hours(normal range is less than 80 mg per day). ANA was positive with a titer of 1:80 and a homogeneous pattern. Complement C3 levels were low with a titer of 83.4 mg/dl.(normal range is 75-135 mg/dl). She was advised a kidney biopsy. Histopathology of the kidney revealed increased mesangial cellularity and increased cellular proliferation in few glomeruli with mild basement membrane thickening. There was no evidence of tubular casts, interstitial inflammation or blood vessel thickening [Figure 6]. Immunofluorescence showed moderate peripheral coarse granular IgG, IgA and C3 deposits with weak IgM deposits. IgA and IgM showed fluorescence in tubular casts. C3 showed fluorescence in blood vessels. The features were suggestive of early stage membranous glomerulopathy (WHO stage V). The patient was started on prednisolone 40 mg, tacrolimus 1.5 mg twice daily and ramipril10 mg for one month. With the above treatment 24 hour urine protein decreased to 744 mg of protein per 24 hours. Tacrolimus was tapered to 1 mg twice daily and prednisolone to 30 mg. The skin lesions subsided completely over a period of 2 months.

Figure 6

Histopathological section from kidney showing increased mesangial cellularity and increased cellular proliferation in few glomeruli with mild basement membrane thickening. Interstitial inflammation and blood vessel thickening was seen. (H and E 40X)

Discussion

An association of erythema multiforme and LE was first noted by Scholtz in 1922. In 1963, during a study of 120 patients with discoid LE, Rowell et al. found four patients to have distinctive clinical and immunologic findings that included erythema multiforme-like lesions, chilblain-like lesions, speckled pattern of antinuclear antibodies, positive serum rheumatoid factor, and antibodies to saline extract of human tissues (Anti SJT positivity).

Of the characteristic immunological abnormalities speckled pattern of ANA was the most preserved. Rheumatoid factor (RF) was the least well preserved. Anti-SJT positivity has been replaced by anti-Ro and anti-La positivity.[2]

In 2000, Zeitouni et al. redefined Rowell's syndrome with major and minor criteria.[3]

Major criteria included

LE: acute, subacute or discoid

Erythema multiforme like lesions (with/without involvement of the mucous membranes),

Speckled pattern of ANA.

Minor criteria were

Chilblains,

Anti-Ro antibody or anti-La antibody,

Positive RF.

Our patient satisfied all three major and one of the minor of the above criteria and also satisfied four of the ACR criteria for SLE. Though originally described in cases of DLE, there is now evidence to classify Rowell's syndrome as a type of subacute LE rather than a separate entity.[4] The early annular polycyclic lesions of SCLE may resemble erythema multiforme with similar histopathological and immunologic findings.[56] Rowell's syndrome has been described with all subtypes of LE (systemic, acute, subacute or discoid). Dysregulated apoptosis is the cause for manifestation of LE and EM skin lesions. Unidentified HSV, EBV or other viral infections may cross-react with lupus autoantigens and they can initiate the immunologic response, hence triggering the EM like lesions in SLE. Similarly, immunopathogenetic mechanisms described in both diseases may be responsible for the co-occurrence.[7]

Anti-Smith (Sm) and anti-ds-DNA antibodies are considered to be nephritogenic and their correlation with lupus nephritis (LN) has been well established. Patients with drug-induced LN (hydralazine) have been described in the literature to have negative ds-DNA and anti-Sm antibodies on serological screening.[8]

Our patient, however, had no evidence of drug induced LN. Only seven cases of non-drug-induced severe LN with negative ds-DNA antibodies are reported.[91011] This is the first report of skin involvement in such patients. Progression of Rowell's syndrome to ds-DNA negative LN has not been reported in the literature. Nail changes seen at presentation when the patient only had features of Rowell's syndrome have not been documented in previously reported cases.

What is new?

Nail changes as seen in our case have not yet been described with Rowell's syndrome

Our case developed lupus nephritis and was ds-DNA negative. ds-DNA negativity has not been described in non-drug-induced lupus with cutaneous features.