(Utmcal and Experimental Dermatology 1992; 17: 137 139.
Urticarial Vasculitis, IgA deficiency and Ci esterase inhibitor deficiency in the presence of an IgG monoclonal gammopathy—a case report R.A.ASHERSON, N.M.M.BUCHANAN, D.D'CRUZ AND G.R.V.HUGHES the Lupus Arthritis Research Unit, The Rayne Institute, St Thomas' Hospital, London SEI 7EH UK Accepted for puhhcation V) ^uly
Summary A female patient, currently aged 40, has attended our Lupus Clinic for 8 years with a clinical picture of urticarial vasculiris, joint pains, severe myalgias and abdominal pain which has occurred in bouts at irregular intervals. She has been found lo have consistently reduced C4 levels, (^5-csterasc inhibitor deficiency and a persistent monoclonal band in the gamma region on elcctroplioresis. Her scrum IgA level has been continuously low. Her symptoms have failed to respond to antihistamines and a variety of other measures but have been partially alleviated by immunosuppressivc therapy ('pulsed' cyclophosphamide). We believe that this is the first patient described showing this combination of clinical and laboratory features. A variety of unusual serological changes in immunoglobulins and complement levels have been reported in association with cutaneous urticaria! \asculitis. Isolated case reports have been reviewed b\ Hijjhet' and two case reports with literature reviews are documented by Ciclfand- and Hentges.' Although rare, these ;i.ssociarions merit careful examination in view of the light that they may he able to shed upon important pathophysiological mechanisms which may be of importance in more common disease processes. We describe a patient with urticarial vasculitis. complement deficiency, a monoclonal paraproteinaemia, and IgA deficiency, the latter association heing hitherto unreported. Case report A 32-year-old women attended the J,upus Clinic at St Thomas' Hospital in 1982. She presented a 3-month history of intermittent abdominal pain occurring for
periods ot up to 10 days which settled spontaneously on each occasion. The pain was l(>cated centrally in the abdomen and was accompanied by nausea and occasional vomiting. Other symptoms jnc^luded anorexia, night sweats and malaise. She had also noticed ill-defined joint pains, particularly in both knees and ankles which were not characterized by morning stifT'ness., but were associated with swelling. There were also severe muscular aches which were most apparent in the calves. A prominent erythematous rash with an urticarial element developed on the limbs particularly on the extensor aspects and especially on the thighs. The lesions were itchy and intermittently coin-shaped or contiguous, covering areas 3 5 cm in diameter. Small vesicles containing clear fluid were scattered over the erythematous area. Episodes ofthe rash lasted up to 10 days. There menon or indeed any of the other characteristic symptoms of Systemic Lupus Erythematosus. Each episode was preceded hy a mild sore tht'oat and llu-like symptoms. She had lost about 18 Ib since the illness began. On clinica! examination the patient was apyrexial and had a normal pulse and blood pressure. She appeared pale and there was pitting oedema extending from the ank!es to the mid-calf !evel. Prominent raised erythematous lesions 1 cm in diameter were present on the thighs and shoulders. These blanched on pressure and were tender to the touch. The ca!f muscles \vere exquisitely tender and there was a mild synovitis of both knees. The range of movement of the right shoulder was reduced and there was tenderness on attempted interna! rotation. Examination of the heart, respiratory system, gastrointestina! and central nervous systems, failed to reveal additional abnormal si^ns. On admission the patient had a low haemoglobin at 8 7 g/d! (this had been 114 g/dl 1 nionth previously). The anaemia was normochromic and normoc\tic and levels of iron, FJ12 and f()!ate were norma!. White-ce!! count and p!atelets were normal, how^ever, the lymphocyte count was low at l-OxlO/l. Serum electrolytes, urea and 137
138
R.A.ASHKRSON et al.
crcatinine were normal but the albumin was reduced at 28 g/1. Plasma protein clcctrophoresis revealed an IgG paraprolein band which was later characterized as a lambda monoclonal production at a concentration of 3 g/l. IgA was reduced at 0 5 g/1 (o^O 9-3-4) while IgG, 5-4 g/1 («^54-16-l) and IgM 0-8 g/1 {H = 0-S-2-0) were both normal. (Complement studies revealed a marked reduction in (>4 at less than 0-06 g/l (H -()• 14 0-7) and normal C., at 1 -72 g/ 1 (»^o-7-l-8). CH50 was less than 1^% (n-50-l25) while the alternative pathway recorded 123So activity (tt^60-14()). Ci-esterase inhibitor was low at 0-05 g/l (K = 0-18-0-26) and rheumatoid factor, antinuclear antibody, Crithidia DNA and antibodies to extractable nuclear antigens (KXA) were consistently negative. Hepatitis-B surface antigen was negative as were the direct Coombs' test and eryoglobulins. More recently, we have also demonstrated a negative anticardiolipin antibody, lupus anticoagulant but a strongly positive antineutrophilic cytoplasmie antibody (AN^CA) [RIA 67',*,, {n < I6'^'o) and positive immunofluorescence |. During the initial illness, the patient's ESR was 100 mm/first hour and she had a raised CRP at 16 mg/1 ( « ^ < 1 0 mg/1). Muscle enzymes were normal. Radiographs ofthe painful joints and ehest were unremarkable and electromyography demonstrated non-specifie myopathie changes with no evidence of denervation or of poivmyositis. Skin biopsy revealed a widespread inflammatory cell infiltrate in the sub-dermis. Small vessels in the dermis demonstrated perivaseular infiltration with polymorphonuelear cells, some with fragmented nuclei. Fibrinoid necrosis was evident in several dermal vessels. These represent the histologieal features of leucoeytoclastie vaseulitis. The patient was treated in the first instance with prednisolone which was maintained at a dose of 20 mg/d. Her symptoms settled rapidly but the biochemical and serological abnormalities did not change. She was transfused with three units of blood and the haemoglobin level was subsequently maintained at between 11 and 12 g/dl. Since her initial presentation, the patient has had irregular recurrences of her symptoms at about 6monthly intervals. The cutaneous features have recurred universally and resolve spontaneously with bruising, as has the arthralgia, but additional symptoms have ineluded pleuritic chest pain and bilateral episcleritis. Tenderness over the right facial artery and temporomandiular joint pain have been occasional features. With prednisolone failing to control the attacks of urticaria, various agents have been tried including antihistamines, cimetidine, dapsone, colchicine, azathioprine, hydroxychloroquine and danazol but none has had any significant clinieal or serologieal eflect. Pulses of eyclophosphamide at doses of between 250 mg and 500 mg have been used in acute attacks with partial benefit only. During attacks, circulating immune complexes have
been raised up to levels as high as 12 9 mg IgCi/dl [n— , Brilish Journal of Dcrmatolog^y 1978; 99: (suppl. 16) 39, 5. Hauptmann (i, Lang J M , \ o r l h MT. cl al. Lyniphosarcama, cold urticaria, TgCil monoclonal cr\
Urticarial Vasculitis, IgA deficiency and Ci esterase inhibitor deficiency in the presence of an IgG monoclonal gammopathy—a case report R.A.ASHERSON, N.M.M.BUCHANAN, D.D'CRUZ AND G.R.V.HUGHES the Lupus Arthritis Research Unit, The Rayne Institute, St Thomas' Hospital, London SEI 7EH UK Accepted for puhhcation V) ^uly
Summary A female patient, currently aged 40, has attended our Lupus Clinic for 8 years with a clinical picture of urticarial vasculiris, joint pains, severe myalgias and abdominal pain which has occurred in bouts at irregular intervals. She has been found lo have consistently reduced C4 levels, (^5-csterasc inhibitor deficiency and a persistent monoclonal band in the gamma region on elcctroplioresis. Her scrum IgA level has been continuously low. Her symptoms have failed to respond to antihistamines and a variety of other measures but have been partially alleviated by immunosuppressivc therapy ('pulsed' cyclophosphamide). We believe that this is the first patient described showing this combination of clinical and laboratory features. A variety of unusual serological changes in immunoglobulins and complement levels have been reported in association with cutaneous urticaria! \asculitis. Isolated case reports have been reviewed b\ Hijjhet' and two case reports with literature reviews are documented by Ciclfand- and Hentges.' Although rare, these ;i.ssociarions merit careful examination in view of the light that they may he able to shed upon important pathophysiological mechanisms which may be of importance in more common disease processes. We describe a patient with urticarial vasculitis. complement deficiency, a monoclonal paraproteinaemia, and IgA deficiency, the latter association heing hitherto unreported. Case report A 32-year-old women attended the J,upus Clinic at St Thomas' Hospital in 1982. She presented a 3-month history of intermittent abdominal pain occurring for
periods ot up to 10 days which settled spontaneously on each occasion. The pain was l(>cated centrally in the abdomen and was accompanied by nausea and occasional vomiting. Other symptoms jnc^luded anorexia, night sweats and malaise. She had also noticed ill-defined joint pains, particularly in both knees and ankles which were not characterized by morning stifT'ness., but were associated with swelling. There were also severe muscular aches which were most apparent in the calves. A prominent erythematous rash with an urticarial element developed on the limbs particularly on the extensor aspects and especially on the thighs. The lesions were itchy and intermittently coin-shaped or contiguous, covering areas 3 5 cm in diameter. Small vesicles containing clear fluid were scattered over the erythematous area. Episodes ofthe rash lasted up to 10 days. There menon or indeed any of the other characteristic symptoms of Systemic Lupus Erythematosus. Each episode was preceded hy a mild sore tht'oat and llu-like symptoms. She had lost about 18 Ib since the illness began. On clinica! examination the patient was apyrexial and had a normal pulse and blood pressure. She appeared pale and there was pitting oedema extending from the ank!es to the mid-calf !evel. Prominent raised erythematous lesions 1 cm in diameter were present on the thighs and shoulders. These blanched on pressure and were tender to the touch. The ca!f muscles \vere exquisitely tender and there was a mild synovitis of both knees. The range of movement of the right shoulder was reduced and there was tenderness on attempted interna! rotation. Examination of the heart, respiratory system, gastrointestina! and central nervous systems, failed to reveal additional abnormal si^ns. On admission the patient had a low haemoglobin at 8 7 g/d! (this had been 114 g/dl 1 nionth previously). The anaemia was normochromic and normoc\tic and levels of iron, FJ12 and f()!ate were norma!. White-ce!! count and p!atelets were normal, how^ever, the lymphocyte count was low at l-OxlO/l. Serum electrolytes, urea and 137
138
R.A.ASHKRSON et al.
crcatinine were normal but the albumin was reduced at 28 g/1. Plasma protein clcctrophoresis revealed an IgG paraprolein band which was later characterized as a lambda monoclonal production at a concentration of 3 g/l. IgA was reduced at 0 5 g/1 (o^O 9-3-4) while IgG, 5-4 g/1 («^54-16-l) and IgM 0-8 g/1 {H = 0-S-2-0) were both normal. (Complement studies revealed a marked reduction in (>4 at less than 0-06 g/l (H -()• 14 0-7) and normal C., at 1 -72 g/ 1 (»^o-7-l-8). CH50 was less than 1^% (n-50-l25) while the alternative pathway recorded 123So activity (tt^60-14()). Ci-esterase inhibitor was low at 0-05 g/l (K = 0-18-0-26) and rheumatoid factor, antinuclear antibody, Crithidia DNA and antibodies to extractable nuclear antigens (KXA) were consistently negative. Hepatitis-B surface antigen was negative as were the direct Coombs' test and eryoglobulins. More recently, we have also demonstrated a negative anticardiolipin antibody, lupus anticoagulant but a strongly positive antineutrophilic cytoplasmie antibody (AN^CA) [RIA 67',*,, {n < I6'^'o) and positive immunofluorescence |. During the initial illness, the patient's ESR was 100 mm/first hour and she had a raised CRP at 16 mg/1 ( « ^ < 1 0 mg/1). Muscle enzymes were normal. Radiographs ofthe painful joints and ehest were unremarkable and electromyography demonstrated non-specifie myopathie changes with no evidence of denervation or of poivmyositis. Skin biopsy revealed a widespread inflammatory cell infiltrate in the sub-dermis. Small vessels in the dermis demonstrated perivaseular infiltration with polymorphonuelear cells, some with fragmented nuclei. Fibrinoid necrosis was evident in several dermal vessels. These represent the histologieal features of leucoeytoclastie vaseulitis. The patient was treated in the first instance with prednisolone which was maintained at a dose of 20 mg/d. Her symptoms settled rapidly but the biochemical and serological abnormalities did not change. She was transfused with three units of blood and the haemoglobin level was subsequently maintained at between 11 and 12 g/dl. Since her initial presentation, the patient has had irregular recurrences of her symptoms at about 6monthly intervals. The cutaneous features have recurred universally and resolve spontaneously with bruising, as has the arthralgia, but additional symptoms have ineluded pleuritic chest pain and bilateral episcleritis. Tenderness over the right facial artery and temporomandiular joint pain have been occasional features. With prednisolone failing to control the attacks of urticaria, various agents have been tried including antihistamines, cimetidine, dapsone, colchicine, azathioprine, hydroxychloroquine and danazol but none has had any significant clinieal or serologieal eflect. Pulses of eyclophosphamide at doses of between 250 mg and 500 mg have been used in acute attacks with partial benefit only. During attacks, circulating immune complexes have
been raised up to levels as high as 12 9 mg IgCi/dl [n— , Brilish Journal of Dcrmatolog^y 1978; 99: (suppl. 16) 39, 5. Hauptmann (i, Lang J M , \ o r l h MT. cl al. Lyniphosarcama, cold urticaria, TgCil monoclonal cr\
