Rh disease (also Rhesus disease, Haemolytic Disease of the Newborn (HDNB) or Morbus haemolyticus neonatorum or erythroblastosis) is a condition that occurs when a Rh negative mother has given birth to a Rh positive baby and subsequently becomes pregnant with another Rh positive child. About 5% of at-risk pregnancies would result in still births or extremely sick babies. Many who managed to survive would be severely retarded. Once a woman gives birth to a baby with the disease, all subsequent babies would also have it. The connection between the Rh antigen and erythroblastosis was made in 1941 by Dr. Philip Levine. The treatment that came to be developed for the disease was blood transfusion, which was often ineffective or only partially ameliorative because the damage had already been done. Severely retarded children often resulted.

During the first pregnancy and the act of birth a small amount of the baby's blood may enter the mother's body. If the mother is Rh negative, her body produces antibodies (including IgG) against the Rhesus antigens on her baby's erythrocytes, if the baby is Rh positive. During the second pregnancy the IgG is able to pass through the placenta into the fetus, where it leads to agglutination and destruction of erythrocytes. The means to prevent this harmful disease is to vaccinate the mother immediately after the birth of her first child: she is treated with anti-Rh antibodies, so that the fetal erythrocytes are destroyed before her immune system can discover them.

This explanation of the etiology of the disease was first worked in 1960 out by Dr. Ronald Finn, a Liverpool, England native, who applied a microscopic technique for detecting fetal cells in the mother's blood. It lead him to propose that the disease might be prevented by injecting the at-risk mother with an antibody against fetal red blood cells. He proposed this for the first time to the public on February 18, 1960. A few months later, he proposed at a meeting of the British Genetical Society, that the antibody be anti-Rh. Nearly simultaneously with him, a group of researchers from New York City Columbia-Presbyterian Medical Center, John Gorman, Vince Freda, and Bill Pollack came to the same realization, and set out to prove it by injecting a group of male prisoners at Sing Sing Correctional Facility with anti-body supplied by Ortho Pharmaceutical Corporation. Dr. Gorman's daughter-in-law was the first at risk woman to receive a prophylactic injection on January 31, 1964. Clinical trials by the two rival groups, and others quickly confirmed their hypothesis, and the vaccine was finally approved in England and the United states in 1968. Within a year or so, it had been injected with great success into more than 500,000 women. Time magazine picked it as one of the top ten medical achievements of the 1960's. By 1973, it was estimated that in the US alone, over 50,000 baby's lives had been saved.

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Undifferentiated connective tissue disease with various pigmentary patterns: a study of three patients
From Journal of Drugs in Dermatology, 9/1/04 by Iqbal A. Bukhari

Abstract

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.

**********

Introduction

Case 1

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]

Case 2

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]

Case 3

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]

Discussion

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.

References

1. Mosca M, et al. Undifferentiated connective tissue disease: analysis of 83 patients with a minimum follow up of 5 years. Rheumatol 2002 Nov: 29(11):2345-9.

2. Braverman IM. Connective tissue diseases. In: Braverman IM. editor. Skin signs of systemic diseases. Philadelphia: Saunders; 1998, 238-9.

3. Sanchez JL, Vazcues M, Sanchez NP. Vitiligo-like macules in systemic scleroderma. Arch Dermatol 1983;19:129-33.

4. Bolognia JL, Pawelek JM. Biology of hypopigmentation. J Am Acad Dermatol 1988;19:217-55.

5. Villers WJS, Jordan HF, Bates W. Systemic sclerosis sine sclerosis sine scleroderma presenting with vitiligo-like depigmentation and interstitial pulmonary fibrosis. Clin Exp Dermatol 1992;17:127-31.

6. Ortonne JP, Perrot H. Scleroderma: ultrastructural study of the melanin pigmentary disturbances of the skin. Clin Exp Dermatol 1980;5:13-25.

7. Krieg T, Meurer M. Systemic scleroderma: clinical and pathological aspects. J Am Acad Dermatol 1988;18:457-81.

8. Alarcon GS. Unclassified or undifferentiated connective tissue disease. Baillieres Best Pract Res Clin Rheumatol. 2000;14(1):125-37.

9. Bodolay E, et al. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol 2003; 21(3):313-20

10. Cavazzana I, et al. Undifferentiated connective tissue disease with antibodies to Ro/SSa: clinical features and follow-up of 148 patients. Clin Exp Rheumatol. 2001;19(4):403-9.

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

ASISSTANT PROFESSOR

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

Phone: +1196638957886

Fax: +1196638949209

E-mail: consultant@dermatologyclinics.net

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