Undifferentiated connective tissue disease (UCTD) is a condition characterized by the presence of clinical manifestations suggestive of a connective tissue disease and at least one non-organ specific autoantibody. In this report I am presenting three types of cutaneous pigmentary changes are presented in three patients which were the clue to the diagnosis of UCTD.
Undifferentiated connective tissue disease (UCTD) refers to a cluster of systemic disorders characterized by clinical manifestations suggestive of a connective tissue disease and the presence of at least one non-organ specific autoantibody (1). Specifically pigmentary changes occur in systemic sclerosis (SS) can be one of three patterns: (1) generalized hyperpigmentation (2) focal hyper-or hypopigmentation in areas of sclerosis and (3) vitiligo-like macules with patches of perifollicular repigmention (2,3). Here I am reporting three of our patients who presented with pigmentary changes similar to those seen in SS and positive autoantibodies which lead us to the diagnosis of UCTD.
A 40-year-old Saudi female presented with a one year history of localized bilateral symmetrical depigmented areas on both shins of her legs. She was diagnosed as a case of vitiligo and was started on topical steroid treatment but with no improvement. The patient was a known case of hypertension, secondary infertility, depression, and glaucoma since almost six years and was kept on oral hydrochlorothiazide 25 mg, Lozartan 50 mg, and Cipram 40 mg, all once daily. Her family history was negative for similar condition. Skin examination revealed the presence of circular patches of perifollicular pigmentation on a background of complete pigment loss, mimicking depigmenting vitiligo on both shin areas of about 5 X 13 cm in diameter with no signs of atrophy or telangiectasias (Figure 1). The patient had no history of joint pain or respiratory complaints. Her investigation revealed erythrocyte sedimentation rate of 45 mm/hr, c-reactive proteins positive, antinuclear antibodies titer of 1:1280 of centromere pattern, antidouble stranded DNA titer of 1:20, Rh factor titer of 64 IU/ml, positive anti-extractable nuclear antibody-RO type and abnormal urine analysis with hematuria and proteinuria. On the other hand the following investigations were negative or normal; complete blood count, fasting blood sugar, renal function tests, liver function tests and anti-extractable nuclear antibodies of SM. RNP, LA, Jo-1, Scl-70 types. Biopsy from the lesion of the skin revealed atrophic epidermis with focal absence of melanocytes at the basal layer proved by S100 protein and sclerosis of collagen at the papillary and reticular dermis with pigmentary incontinence. So the patient was diagnosed as a case undifferentiated connective tissue disease with vitiligo-like lesions as the only clinical sign of her disease. She was kept on Daivonex ointment twice a day and topical psoralen with UVA exposure three times per week for six months but unfortunately she did not respond instead the lesions remained stationary. Now the patient is regularly followed up since 5 years without any new signs of connective tissue disease.
[FIGURE 1 OMITTED]
An 18-year-old Saudi male presented with two years history of scattered patches of hypopigmented areas on the upper and lower extremities (Figure 2). At the beginning he was clinically diagnosed as a case of vitiligo versus pityriasis alba and was started on topical steroid treatment but with no improvement. The patient was a known case of atopic dermatitis. His family history was negative for a similar condition. Skin examination revealed the presence of hypopigmented circular patches on the upper and lower extremities with no signs of atrophy or telangiectasias. The patient had no systemic complaints. His investigation revealed normal complete blood count and erythrocyte sedimentation rate with negative c-reactive proteins, antinuclear antibodies, antidouble stranded DNA, Rh factor and anti-extractable nuclear antibodies of SM, RNP, LA, Jo-1, Scl-70 types. However he had positive anti-extractable nuclear antibody-RO. Biopsy from one of the lesions on the legs revealed focal atrophy of the epidermis with focal reduction of the melanocytes at the basal layer proved by S-100 immunostaining. The dermis was markedly thickened and collagenous with absence of skin adnexae. So the patient was diagnosed as a case undifferentiated connective tissue disease with hypopigmented lesions. He was kept on Daivonex ointment and medium potency topical steroid twice a day for 12 months with no change. The patient is not currently on any treatment and is irregularly followed up in our clinic since four years without any new signs of connective tissue disease.
[FIGURE 2 OMITTED]
A 45-year-old Saudi female presented with a three years history of patchy facial and neck hyperpigmentation. The patient was a known case of atopic dermatitis on emollients only. Her family history was negative for similar condition and she had no systemic complaints. Skin examination of the face and neck showed patches of hyperpigmented pin head size papules on the forehead, eyelids, chin, sides of the cheeks, and sides of the neck with no telangiectasias or hirsutism (Figure 3). Other sun exposed areas were normal. Wood's light showed dermal type of hyperpigmentation. Her connective tissue profile revealed positive anti-extractable nuclear antibody-RO type and negative anti-extractable nuclear antibodies of SM, RNP, LA, Jo-1, and Scl-70 types. Complete blood count, renal function tests, liver function tests, serum cortisol and thyroid function tests were normal. Biopsy from the lesion of the skin revealed atrophic epidermis with focal absence the basal layer and mild dermal sclerosis with pigmentary incontinence. There was no inflammatory infiltrate and direct immunofluorescent was negative. So our final diagnosis of this case was undifferentiated connective tissue disease with skin hyperpigmentation ruling out lichen planus pigmentosus and postinflammatory hyperpigmentation. The patient was kept on topical bleaching agent twice a day and now she is regularly followed up in the clinic with periodic systemic evaluation.
[FIGURE 3 OMITTED]
Undifferentiated connective tissue disease (UCTD) refers to a cluster of systemic disorders characterized by clinical manifestations suggestive of a connective tissue disease and the presence of at least one non-organ specific autoantibody (1). Interestingly, the pigmentary changes in the skin usually occur in systemic sclerosis (SS) which can be one of three patterns: (1) generalized hyperpigmentation simulating adrenal insufficiency (2) focal hyper-or hypopigmentation in areas of sclerosis and (3) chalk-white vitiligo-like macules with patches of perifollicular repigmentation (salt and pepper pattern) with dermal sclerosis most commonly found on the upper part of the trunk and the distal parts the extremities (2,3). In fact, the third pattern is considered to be a variant of ordinary vitiligo and has similar histological, histochemical, immunopathologic and electron microscopic findings (4). Clinically, in both diseases the lesions are characterized by chalk-white macules with perifollicular repigmentation, well-defined borders located over the extensor bony surfaces but tend to be more focal, stable, and symmetrical in SS5. In SS, suggested pathogenesis of these depigmented lesions is T-lymphocyte-mediated melanocyte damage similar to the autoimmune hypothesis of vitiligo (2,3,5,6), while postinflammatory response in areas of sclerosis is thought to give rise to local hyperpigmentation and hypopigmenuation (7). Each of our patients was representing one type of those pigmentary changes seen in SS proven by biopsy. In addition, there was positive anti-dsDNA in the first patient and anti-ENA-SSA (Ro) in all while systemic evaluation did not reveal any major organ involvement. So our patients were labeled as having UCTD. Possible outcomes for those patients include remaining undifferentiated, differentiating into a defined CTD or going into remission (8). In the five year follow up of patients with UCTD conducted by Bodolay et al the highest probability of evolution to a defined CTD was during the first two years with one third of the UCTD patients showed progression into different types of specific CTD (9). However, Cavazzana et al found that 24.3% of their patients with UCTD and antibodies to Ro/SSA progressed to well defined CTDs over a period of 4.5 years with the development of primary SS predicted by xerophthalmia and SLE by the appearance of anti-dsDNA antibodies (10). It was also suggested by Belfiore et al that analysis of anti Ro(SS-A) specificity may provide useful information for predicting the course of UCTD. In other words, autoantibodies to Ro(SS-A) may recognize two different polypeptides, of 52 kDa and 60 kDa with most of the patients with SLE or Progressive SS having both anti-52 kDa and -60 antibodies; isolated anti-60 kDa antibodies were found in SLE patients and in none of the Progressive SS patients, whereas high titers of anti-52 kDa were more common in the Progressive SS than in the SLE patients (11). On the contrary in the UCTD patients, the anti-Ro(SS-A) profile showed no significant correlations with clinical features but was associated with the clinical outcome as reported by Belfiore et al in their 12 patients who had isolated anti-52 kDa 11. Unfortunately, we could not determine which type of anti-Ro(SS-A) present in our patients because it was not available. In conclusion, anti Ro(SS-A) might be occurring more frequently with pigmentary skin changes associated with systemic sclerosis which in turn could indicate that this test preferably be included in the initial blood tests requested in any patient presenting with such pigmentary changes. Further studies are indicated to strengthen that suggestion.
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11. Belfiore N, et al. Anti-RO(SS-A) 52 kDa and 60 kDa specificities in undifferentiated connective disease. Joint Bone Spine 2000;67(3):183-7
IQBAL A BUKHARI MD
DEPARTMENT OF DERMATOLOGY, KING FAISAL UNIVERSITY
COLLEGE OF MEDICINE AND MEDICAL SCIENCES
ALKHOBAR, SAUDI ARABIA
ADDRESS FOR CORRESPONDENCE:
Dr. Iqbal A. Bukhari
King Fahad Hospital of the University
P.O. Box 40189
Alkhobar 31952, Saudi Arabia
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