From Grand Rounds from HSS: Management of Complex Cases | Volume 7, Issue 3
A 53-year-old woman presented with a rash that had recurred intermittently on the lower extremities over 2 years. She reported that it was never itchy or palpable and would resolve spontaneously. Her medical history included renal tubular acidosis, polyclonal hypergammaglobulinemia (immunoglobulin [Ig] G, 4080 mg/dL), and multiple positive autoimmune serologies (anti-nuclear antibodies [ANA], 1:1280, speckled; anti-Ro and anti-La antibodies, both > 100 EU/mL; rheumatoid factor [RF], 89 IU/mL), as well as an intermittently elevated erythrocyte sedimentation rate (ESR) to 146 mm/hr and low complements (C4, 7.5 mg/dL). Review of symptoms was negative for dry eyes or mouth, arthritis, parotid hypertrophy, or lymphadenopathy.
Examination revealed non-palpable bilateral lower-extremity petechiae, with surrounding erythema and areas of post-inflammatory changes (Fig. 1). Laboratory testing was negative for cryoglobulins and antiphospholipid antibodies. Skin biopsy revealed both superficial and deep dermal neutrophilic infiltrate with erythrocyte extravasation. Immunofluorescence demonstrated significant complement deposition. Based on the clinical and pathological appearance of the rash, the presence of high inflammatory markers, and the patient’s history of hypergammaglobulinemia, she was diagnosed with hypergammaglobulinemic purpura of Waldenström (HGPW).
Figure 1: Appearance of rash prior to therapy
Hydroxychloroquine (HCQ) was started at 200 mg twice daily for the petechiae, but after 2 months with no noticeable effect it was stopped in favor of dapsone 25 mg twice daily, with significant improvement (Fig. 2).
Figure 2: Appearance of rash after initiation of dapsone.
HGPW, first described in 1943, involves a combination of recurrent lower-extremity petechiae/purpura, elevated ESR, and polyclonal gammopathy . Episodes of purpura may be triggered by increased hydrostatic forces in the lower extremity such as tight clothing or exercise and preceded by mild burning, itching, or pain. The purpura fades over days but can result in residual hyperpigmentation, and the frequency of attacks can range from days to months. Primary HGPW affects young women and can be associated with anti-Ro antibodies, leading to pregnancy complications such as intrauterine growth restriction and neonatal heart block . Secondary HGPW affects older adults and is associated with Sjögren’s syndrome (SS), systemic lupus erythematosus, rheumatoid arthritis, infection, and malignancy. Laboratory findings include mild anemia, elevated ESR, positive RF, polyclonal hypergammaglobulinemia (usually elevated IgG but at times also IgA and IgM), positive ANA, and anti-Ro antibodies .
It is thought that the pathogenesis relates to the polyclonal gammopathy, with RF-containing immune complex formation and deposition in blood vessels. Histopathology findings can include erythrocyte extravasation, perivascular lymphocytic infiltrates, and leukocytoclastic vasculitis, while immunofluorescence reveals immune complexes in the vessel wall.
Although generally benign and asymptomatic and therefore left to resolve spontaneously, HPGW can be managed by compression stockings, systemic glucocorticoids for severe cases, and indomethacin or HCQ for milder cases . Despite no published studies supporting dapsone use in HGPW, it was chosen in this case because it is used in cutaneous vasculitis, such as leukocytoclastic vasculitis, which, as it was in this case, is often neutrophil mediated . Our patient demonstrated many of the above features, including the presence of anti-Ro and anti-La antibodies, raising suspicion for SS. Although dry eyes or mouth were not present, the patient had a history of distal renal tubular acidosis, which has been described in up to 14% of SS patients , suggesting this case may represent a forme fruste of SS.
Jonathan T.L. Cheah, MBBS
Hospital for Special Surgery