Department of Internal Medicine I, Division of Rheumatology and Clinical Immunology, University Hospital of Regensburg, D-93042 Regensburg, Germany
SIR, We report a 49-yr-old female patient presenting with symmetrical polyarthritides involving proximal interphalangelal (PIP) joints, metacarpophalangeal (MCP) joints, wrists, ankles and metatarsophalangeal (MTP) joints. The patient had been diagnosed with Heberden's and Bouchard's disease 5 years previously. At the time of first visit, the patient presented in reduced condition, with impressive swelling of all PIPs and all distal interphalangeal (DIP) joints, and less swelling of MCPs II and III. Laboratory results revealed an ESR of 15/22, a CRP of 17.1 mg/l (normal <5 mg/l) and an RF of 421 U/ml. HLA-DR4 was positive. X-rays of hand and finger joints showed joint narrowing of all PIPs and DIPs with minor erosions in PIPs III and IV. A skeletal scintigraphy revealed tracer accumulation in all DIPs, PIPs, MCPs and the left wrist. Based on the ACR criteria for rheumatoid arthritis (RA) [1], the diagnosis of RA in addition to Heberden's and Bouchard's disease was made. Initial therapy consisted of 50 mg prednisolone/day and 75 mg diclofenac b.i.d. for pain relief.
One month later, during tapering prednisolone, joint pain and swelling had increased again, and a standard DMARD therapy with oral methotrexate (MTX) 15 mg/week was initiated.
After 2 months, articular pains had decreased considerably, and clinical examination showed swelling of all PIPs including PIP I. Owing to chest pain, the patient was hospitalized and the following laboratory results were found (normal values in parentheses): ESR 8/30 mm, CRP 14 mg/l, haemoglobin 16.3 g/dl (11.715.7 g/dl), LDH 319 U/l (120240 U/l), AST 19 U/l (<15 U/l), ALT 52 U/l (<17 U/l) gamma-GT 26 U/l (418 U/l), iron 184 µg/dl (60150 µg/dl), ferritin 1140 ng/ml (10120 ng/ml), transferrin 179 mg/dl (200360 mg/dl) and transferrin saturation 73% (1645%). Duplex ultrasound of the lower extremity veins revealed a partial thrombosis of the left superficial vein. To further clarify the origin of the polyglobulinemia, a liver biopsy was performed and showed fatty changes and discrete parenchymal and mesenchymal siderosis, but not the classical picture of haemochromatosis. Quantitatively, however, liver iron was highly increased, at 1599 µg/g (<900 µg/g). Genetic analysis revealed a HLA-H Cyst-282Tyr mutation (HLA-H His 63 Asp wt/wt), the diagnosis of familiar haemochromatosis could then be established and MTX was discontinued.
Three months later, the patient still complained of joint swelling of PIPs and articular pain in wrists, MCPs, ankles and MTPs, and leflunomide (20 mg/day) in combination with rofecoxib was started. Of interest, the recommended phlebotomies had not been performed for 3 months. Subsequently, laboratory results showed a reduced inflammatory activity (ESR 9/29, CRP 6.5 mg/l), but increasing iron metabolism parameters (iron 173 µg/dl, ferritin 932 ng/ml, transferrin 168 mg/dl, transferrin saturation 58%).
Nine months later, the patient again complained about pain and swelling in PIPs, the right MCP I and the left wrist. Two weeks earlier, she had discontinued leflunomide due to chest pain. Laboratory results showed a slightly increased disease activity (ESR 20/45, CRP 19 mg/l). Whereas the iron value had increased again [136 µg/dl (60150 µg/dl)], ferritin levels continued to decrease [199 ng/ml (10120 ng/ml)] due to regular phlebotomies. As the clinical symptoms still persisted and the inflammatory disease activity had increased again, a DMARD therapy with etanercept was started, and was followed by a decrease in clinical and serologic activity of RA.
This report describes the unusual co-incidence of Heberden's and Bouchard's osteoarthritis, RA and familiar haemochromatosis in a 49-yr-old female patient within a short period of time. Joints affected predominantly by RA are MCPs and PIPs, whereas the predilection sites of finger osteoarthritis are DIPs (Heberden's disease) and PIPs (Bouchard's disease) [2]. Application of the respective classification criteria showed the presence of both diseases in our patient. Familiar haemochromatosis as the most common autosomal recessive hereditary disease, with a prevalence of 1:400 in Europe, is frequently underestimated as a cause of arthropathies [3]. It is caused by a homocygeous mutation of the HFE gene on chromosome 6 [4].
Radiologically, the typical signs of Heberden's and Bouchard's osteoarthritis could be documented in our patient at the DIP and PIP joints. In addition, the marginal erosions in the PIPs could have also been an initial sign of RA. When evaluating bone scintigraphy, discrete tracer accumulations were seen in some of the MCP/MTP joints, supporting the diagnosis of RA [1].
Articular symptoms are frequent manifestations of hereditary haemochromatosis (30% of the patients), sometimes even constituting the first symptoms of the disease [3]. Typically, MCP joints II and III are involved radiologically, often presenting as an osteoarthritis-like picture [3]. In our case, these articular alterations could not be seen. Even though there have been reports on patients in which hereditary haemochromatosis was masquerading as RA [5], in our patient, these two entities could be well differentiated due to the following reasons: first, RA was diagnosed according to the established criteria; secondly, development of pathological laboratory values of iron metabolism occurred definitely after the diagnosis of RA; thirdly, RA as chronic inflammatory disease is usually characterized by a normocytic, normochromic anaemia associated with reduced serum iron and transferrin saturation; fourthly, symptoms of RA improved during therapy with corticosteroids and MTX and worsened after discontinuation of MTX; and finally, even though phlebotomy as therapy for haemochromatosis was unfortunately not started until 6 months after its diagnosis, there was no correlation between the degree of articular symptoms and the concentration of iron and ferritin (see Fig. 1). Thus, it can be concluded that in this patient clinically active RA (plus Heberden's and Bouchard's osteoarthritis) was associated with haemochromatosis.
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Nevertheless, the possibility that high iron values may have modulated the inflammatory activity of RA can not be ruled out as long as these values were not lowered to a therapeutic level (ferritin <50 ng/ml) [7]. In line with this hypothesis, it has long been known that disease-modifying drugs such as MTX or ciclosporine are capable of increasing serum iron levels in arthritis [8]. Iron, in turn, is known to catalyse oxidative radical reactions with subsequent formation of hydroxyl radicals and lipid peroxidation, which both can cause inflammatory tissue damage [9]. Moreover, iron has been demonstrated to stimulate DNA synthesis of synovial cells and to exhibit an additive effect on synovial cell proliferation, together with cytokines such as interleukin-1ß or TNF-, underlining the role of iron itself in the modulation of disease activity of RA [10]. The hypothesis, therefore, would be that treatment of RA with MTX resulted in an increase of serum iron values that demasqued an underlying so far latent haemochromatosis, and led to its manifestation (see Fig. 2
).
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Notes
Correspondence to: J. Schedel. E-mail: joerg.schedel{at}klinik.uni-regensburg.de
References