Pyoderma gangrenosum and Rheumatoid Arthritis With Massive Necrotic Ulcer of the Right Foot

Pyoderma gangrenosum (PG) is associated with systemic disease, mostly rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), in many patients (more than 50%). Lesions associated with arthritis are often ulcerative. Although these lesions typically affect the lower limbs, they can also affect the entire body. Successful therapy involving monoclonal antibodies seems to favor an autoimmune etiopathogenesis that has disorders of neutrophils’ chemotactic activity and interleukins, which are acted upon by TNF-α cytokines. The ulcers grow rapidly, exacerbate after trauma, and necrosis can invade each skin layer up to the fascia. Therefore, debridement is contraindicated because it introduces the so-called “pathergy” mechanism. The diagnosis is quite difficult and is often made late due to the lack of indicative clinical and laboratory findings. The following is a report of a case of multiple, ulcerative, PG ulcers induced by arthritis. The ulcers occurred over several occasions with large and aggressive necrosis reaching the osseous plane in the heel and elbow. The high IgE values (between 2000 UI/mL and 3000 UI/mL) suggested that a type I immunitary reaction, such as in-skin anaphylaxis, was involved. Nevertheless, the antigen remains unknown and the genesis may be multifactorial. A corticosteroid (prednisolone) was the first-line systemic treatment used in this case and caused rapid improvement. Further investigations will be necessary to understand the meaning of this immunologic disorder.

At the beginning of the previous century, the condition of a chronic ulcer stemming from bacterial infection that frequently occurred in association to systemic diseases, such as ulcerative colitis, rheumatoid arthritis (RA), chronic infection, and malnutrition, was described in the literature.¹ First named Brocq’s phagadena geometricum after the French dermatologist Louis-Anne-Jean Brocq who first reported on the disease, it is also commonly known as Meleney’s undermining burrowing ulcer or Cullen’s postoperative serpiginous ulceration. In 1930, the disease was given the name Pyoderma gangrenosum (PG) when it was reported and confirmed as a streptococcal infection.²

Even after a century, the etiology and pathogenesis of the disease remain unknown. It is likely that PG is an aberrant immune response to a not yet identified antigen. There are no indicative clinical and laboratory findings to define PG; therefore, the diagnosis is often late and only reached by exclusion.

Pyoderma gangrenosum is frequently associated with RA, sometimes as high as 37%.³ The association between PG and hyper-IgE is rare,⁴ but high levels of IgE have never been reported in RA-induced PG.

The following case reports on a patient suffering from RA and a myeloproliferative syndrome with aggressive PG of the right foot and subsequently, of the right elbow and penis. The increased IgE level seen in this patient, and the hypothesis of considering the IgE level as a diagnostic parameter in arthritis-induced PG, is highlighted. Once the patient received steroid treatments, positive results were achieved.

In March 2007, a 75-year-old man presented with a massive necrotic ulcer of the medial area of the ankle, heel, and sole of the right foot. The vast necrosis of the heel determined the exposure of the bone. The borders of the ulcer were partially raised, uneven, and purple; the skin was erythematous with infiltration, and edema was affecting half of the leg (Figure 1A).

The ulcer appeared about 10 days before initial presentation. The ulcer grew rapidly and was particularly painful. The origin of the ulcer was not evident. Antalgic therapy was given to the patient first orally and then intravenously, but failed to yield any results.

The patient also had a myeloproliferative syndrome (treated with hydroxyurea 1.5-g daily), a severe form of deforming RA, in desultory therapy with anti-inflammatory drugs and methotrexate, and serious heart disease with several episodes of atrial fibrillation.

Upon admission, the patient was diagnosed with leg ischemia from chronic arteriopathy and was consequently treated with continuous administration of prostaglandins through a single-day elastomer (120 µg/day). Additionally, hydroxyurea administration was interrupted and busulfan (2 mg/day) was added. The x-rays of the foot showed a significant deformation with metatarsus sub-sprain that was caused by the arthritis (Figure 2).

Initial blood tests revealed high levels of leukocytes (WBC: 69.4 x 103/µL, with 64% of neutrophils), normocytic anemia (Hg: 7.7 g/dL), thrombocytopenia (PLT: 66 x 103/µL), hypoalbuminemia (2.1), and kidney failure with hyperazotemia and hypercreatinine (AZO: 62 mg/dL; CRE: 1.57 mg/dL). The rheumatoid factor was elevated (522.7; normal value: 0–14), as were the anti-cyclic citrullinated peptides (anti-CCP: 87.9 UI/mL), and the C-reactive protein (24.10; normal value: 0–0.5). Cultural tests of the biopsy did not show the presence of pathogenic germs. Histological tests of random biopsies revealed necrotic tissue with inflammatory infiltration that was mostly neutrophilic. An ultrasound examination 2 days after initial presentation did not show vascular disease.

Laboratory values progressively worsened 6 days after hospitalization (WBC: 89.1 x 103/µL; PLT: 40 x 103/µL; CRE: 3.27 mg/dL; AZO: 128 mg/dL; after 2 days Hg: 6.8 g/dL), and for this reason, a blood transfusion was performed. The patient’s general condition worsened and pain increased. Dysuria, fever (103.1˚F), and dyspnea developed and the ulcers became necrotic. There were other ulcers with the same characteristics on the right elbow (Figure 3A) and a minor ulcer at the base of the penis (Figure 4A).

The diagnosis of PG was made because of the characteristics and localization of the ulcers, and the clinical history of rheumatoid disease and myeloproliferative syndrome. Corticosteroid therapy (methylprednisolone 40-mg daily) was administered to the patient and his condition improved. After 2 days, there was no pain and the necrosis decreased. Laboratory findings also improved (WBC: 52.5 x 103/µL; PLT: 52 x 103/µL; CRE: 1.39 mg/dL; AZO: 76 mg/dL). After 7 days of therapy, laboratory values were (WBC: 38.2 x 103/µL; PLT: 56 x 103/µL; CRE: 0.8 mg/dL; AZO: 68 mg/dL; RF: 287, RCP: 4).

Initially, the IgE value was particularly high: 2336.01 UI/mL (normal value: 0–100 UI/mL). During the first therapy, IgE elevated to 2762 UI/mL, and later dropped to 1484 UI/mL, which was followed by another decrease to 1113 UI/mL. This pattern of lowering values was observed after 15 and 30 days, as a result of the corticosteroid therapy. The IgM value remained at 112 mg/dL for the entire hospitalization (normal value: 35–210 mg/dL). IgA increased minimally (579 mg/dL initially), but later decreased to 529 mg/dL after 30 days. The serum values of ferritin were also very high (1707 ng/mL), while the IgG (1316 mg/dL; normal value: 640–1400 mg/dL) and the serum C3 and C4 components of complement (83 mg/dL and 23 mg/dL, respectively) were normal. Moreover, after 10 days of corticosteroid therapy, oral therapy with methotrexate was started at 7.5-mg/day.

After 18 days of intravenous cortisone, the therapy was changed to oral prednisone 50-mg/day, divided into two administrations. After 7 days, the patient was discharged on 40-mg/day. Periodic clinical controls showed progressive improvement of the ulcers, which were treated with local medications (Figure 1B, 3B, 4B). A cream containing 0.2% hyaluronic acid and 1% silver sulfadiazine was applied topically.

Pyoderma gangrenosum was described for the first time almost 100 years ago.¹ Today, the etiology and physiopathology of PG are unknown, although the most validated hypothesis considers PG a disease of the immune system, due to the alterations of neutrophils and interleukin through the action of TNF-α cytokines.⁵ Some PG ulcers are described as isolated ulcers, while in most cases, skin ulcers are associated with inflammatory bowel disease (IBD) in 30% of cases and arthritis with a seropositive increase of the rheumatoid factor in 25% of cases (range: 20%–37%).⁵ Pyoderma gangrenosum is seldom associated with other systemic diseases, such as myeloproliferative syndromes, chronic hepatitis, polycythemia, myeloma, or AIDS.^6–8 Exact clinical and instrumental indications for PG do not exist. For this reason, diagnosis is made by excluding other similar diseases (eg, vascular ulcers, Lupus, Wegener’s vasculitis, mycotic and herpetic infections, TBC, or amebiasis).⁷

Pyoderma gangrenosum was not diagnosed at the initial presentation in this case, although the presence of conjoint diseases (myeloproliferative syndrome and RA) was made, following the quick development and extent of the first ulcer. The laboratory tests and development of the other necrotic ulcers contributed in making the correct diagnosis.

Powell et al¹⁰ published epidemiological data on the incidence of the disease (3–10 cases per million annually, with a peak between age 25 and 50 years). They also suggested a clinical classification on the type of ulcers with 4 variants. The ulcers associated with hematological diseases are often bullous, while those associated with arthritis are ulcerative and localized at the legs.⁸ Vegetative forms are uncommon in association to arthritis,¹¹ while pustular forms often appear during IBD.

The foot and elbow ulcers in the presented case were large, severe, irregular, and had risen, asymmetrical borders. The necrotic evolution of the ulcers to the bone exposure was rapid and associated with neutrophilic leukocytosis, fever, strong pain, renal insufficiency, and anemia.

Classic forms of PG associated with arthritis present as aggressive ulcers, which quickly involve the skin, fascia, tendons, and muscles, and typically have a diameter exceeding 10 cm.¹² Moreover, these ulcers have a slower recovery than idiopathic forms, although the therapy is the same.¹³

Cultural tests, performed on the borders and center of the ulcers, did not show any bacterial or mycosis infiltration. Histological tests showed a rich neutrophilic infiltration, while blood tests pointed out hyper-IgE and high levels of ferritin, while IgA levels changed only slightly. The alteration of IgA and IgG levels (75% and 25%, respectively) is described in PG associated to monoclonal γ-disease.¹²

Hyper-IgE in PG is described as one of the congenital causes of immunitary disorders, humoral type, and not the cell-mediate type.⁴ The hyper-IgE syndrome is an uncommon immunodeficiency, most likely autosomic dominant, which is characterized by skin and pulmonary bacterial infections, and bone and dental alterations. These elements were not present in this case. In this disorder, the IgE serum level can increase up to 60,000 UI/mL; such values are considered very high, and therefore, are not comparable to the present case.

Human IgE antibodies are responsible for immediate hypersensibility that constitute initial immune reactions, known as anaphylactic reactions. Anaphylactic reactions release primary mediators such as histamine, and secondary mediators, such as the chemotaxis neutrophilic factor. The high levels of IgE in the serum may be a result of the strong immunitary answer to PG associated with skin anaphylaxis. According to some, the mechanism is the same as Arthus’ reaction where vasculitis surrounds the ulcer due to protein deposits.¹⁴ The patient’s C3 and C4 values were normal and thus, it was not possible to find a cell-mediate immunitary reaction with immunocomplex, as in an Arthus’ reaction.¹⁵ Alternatively, one could presume that another mechanism is involved, such as in atopic dermatitis or in skin anaphylaxis, but the antigen remains unknown.

The first reported case of PG made the connection between bacterial infection and immunity.¹ After 70 years, the causal factor of this alteration remains unknown.¹⁶ Pyoderma gangrenosum most likely has a multifactorial origin and different mechanisms that are dependent on associated systemic diseases. Dosing total IgE levels could help achieve an earlier diagnosis of PG for ulcers suspected to be associated with RA.

Corticosteroid therapy was successful as implemented in the presented case. Local and systemic results were rapid and decreased the pain and fever, improved renal functionality, and ultimately healed the ulcers. Therefore, cortisone, in the authors’ experience, provides the best results for treating PG-related ulcers. Local debridement is not necessary because it can worsen the ulcers and cause so-called “pathergy.”5 Early diagnosis of PG must be made, because in many cases necrotic ulcers tend to have surgical treatment for cleaning purposes.

Address correspondence to:
Fabio Pacifico, MD
Ospedale Sacro Cuore di Gesù–Fatebenefratelli Viale
Principe di Napoli
14/A 82100 Benevento Italy
Phone: 0824 771201
E-mail: fabiopacifico@libero.it