|Year : 2017 | Volume
| Issue : 6 | Page : 189-193
Jyoti Ranjan Parida
Department of Immunology and Rheumatology, IMS and SUM Hospital, Bhubaneswar, Odisha, India
|Date of Web Publication||23-Nov-2017|
Jyoti Ranjan Parida
Department of Immunology and Rheumatology, IMS and SUM Hospital, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
Fibroblastic rheumatism (FR) is a rare dermoarthopathy reported from different parts of the world since 1980. Although the exact cause is unknown, few reports implicate infection may be a triggering event. Patients usually present with multiple skin nodules and polyarthropathy with progressive skin contractures. Laboratory parameters including acute phase reactants are usually normal. The confirmatory diagnosis is based on histopathologic study of skin nodules, which demonstrate fibroblastic proliferation, thickened collagen fibers, dermal fibrosis, and decreased number of elastic fibers. Immunoreactivity for b-catenin, smooth muscle actin, and the monoclonal antibody HHF35 show myofibroblastic differentiation. Treatments with oral prednisolone and other disease-modifying drugs such as methotrexate, infliximab, and interferon have been tried with variable success. In general, skin lesions respond more aptly than joint symptoms indicating that skin fibroblast is more amenable to treatment than synovial fibroblasts. Awareness regarding this orphan disease among clinicians and pathologists will help in more reporting of such cases and finding out optimal treatment regimen.
Keywords: Dermoarthopathy, fibroblastic, polyarthritis, rheumatism, skin nodules
|How to cite this article:|
Parida JR. Fibroblastic rheumatism. Indian J Rheumatol 2017;12, Suppl S1:189-93
| Introduction|| |
Fibroblastic rheumatism (FR) was first described in 1980 from France by Chaouat et al. and thereafter only a few dozens of cases have been reported in literature in the past four decades. FR is characterized by sudden onset of multiple cutaneous nodules with polyarthritis and sometimes skin contractures. The diagnosis is made by biopsy of cutaneous nodules, which shows myofibroblastic proliferation in a background matrix of collagen and decrease in elastic fibers. Although the skin nodules regress after treatment, joint deformity persists. FR should be included in the differential diagnosis of any patient presenting with polyarthritis with multiple skin nodules.
| Epidemiology|| |
The exact prevalence of FR is unknown considering its unawareness among physicians. Although cases have been reported worldwide most cases have been detected among Caucasians.,,, The age onset ranges from 8 to 68 years without any gender predilection. Till date, around nine cases have been reported in children. Only one adult case has been reported from India by our group in 2011, and no cases reported thereafter to the best of to our knowledge. We attribute this to the lack of awareness of this condition among physicians and pathologists.
| Pathogenesis|| |
The exact cause and pathogenesis of FR are unknown. Histopathological studies suggest that FR occurs due to fibroblastic proliferation rather than increased collagen synthesis. The fibroblasts have a greater proliferative ratein vitro as well as reduced secretion of collagen and noncollagenous proteins in FR. This finding is in contradiction to systemic sclerosis, where increased dermal collagen synthesis is observed.
Under which condition the dermal fibroblasts are converted to myofibroblasts is yet to be elucidated. Both exogenous and endogenous factors have been implicated. Many case reports suggest infection as a possible trigger and different infections such as upper respiratory infection, hepatitis C, and Streptococcus have been attributed based on their temporal association. In one child, FR symptoms appeared within 1–2 weeks of hepatitis B infection. Only one case described in a patient suffering from lupus  and another case found to have lung adenocarcinoma  on autopsy. However, these data are insufficient to attribute malignancy or connective tissue disease as a possible trigger or disease association.
Many cytokines may play a role in transdifferentiation of fibroblasts to myofibroblasts. Transforming growth factor-beta and granulocyte macrophage-colony-stimulating factor are known to induce this phenotypic switch. Successful use of anti-tumor necrosis factor (TNF) and infliximab in one patient  indicates TNF-alpha may have a pathogenic role by modulating fibroblast function. Although the exact mechanism of tissue injury in FR is unclear, myofibroblasts are thought to have synthetic, phagocytic, and contractile properties. Factors responsible for transdifferentiation of synovial fibroblasts also stimulate the secretion of matrix metalloproteinases and/or promote collagen phagocytosis by myofibroblasts, leading to joint destruction.
There is a debate in the literature whether to include FR as a non-Langerhans histiocytosis or fibromatosis. In the initial case reports, histopathological specimen showed dermal fibrosis with interspersed histiocytes suggesting classifying FR under non-Langerhans histiocytosis. However later, most immunohistochemical studies showed that most of the spindle-shaped cells in FR were stained with anti-smooth muscle actin (SMA) and anti-calponin antibodies and negative for most histiocytic markers such as CD163 and FXIIIa, suggesting that they should be better classified as fibromatoses.
| Clinical Feature|| |
FR is characterized by the presence of cutaneous nodules and joint symptoms. However, there are two case reports of FR only presenting with cutaneous manifestation without any joint involvement even after long-term follow–up., Systemic or visceral involvement is not reported yet.
The cutaneous nodules are essential to the diagnosis and may precede or follow the musculoskeletal features by weeks to months. These nodules are usually solid, pink, or flesh colored and range from 5 to 20 mm in diameter.,,, They are present in upper and lower extremities with a predilection for periarticular areas such as hands, elbows, knees, ears, and neck. They tend to resolve in 6–24 months with or without treatment. Other cutaneous features are reported in various case reports and include sclerodactyly (76%), thickened palmar fascia (44%), erythematous plaques or papules (28%), and Raynaud phenomenon (36%).
Joint involvement may manifest in any stage of the disease and is many times heralded by the edema of the affected joints. They consist of sudden onset symmetric polyarthritis/polyarthralgia, usually affecting small distal joints of both upper and lower extremities. There are case reports of arthritis affecting large joints (knees, hips, shoulders, and elbows). Initially, FR mostly presents as joint stiffness without any joint destruction. With progression of the disease, articular movement of affected joints becomes markedly restricted and painful and is associated with flexion contractures of the fingers.
| Laboratory Diagnosis|| |
Blood investigations are usually unremarkable in FR. Complete blood count and acute phase reactants are normal, and this helps in differentiating from inflammatory arthritis. All the autoantibodies including rheumatoid factor, anticitrullinated antibody, and antinuclear antibody are absent. These laboratory tests are useful to rule out other diagnoses such as inflammatory arthritis or other connective tissue disorders.
| Histopathology|| |
Biopsy from the cutaneous nodule is unique and diagnostic of FR. Both histopathology and immunohistochemical studies should be ordered. Histopathological studies of this nodule show that epidermis is essentially normal. Dermis shows proliferation of spindle-shaped cells focally arranged in a storiform pattern, thickened collagen fibers, and dermal fibrosis. Weigert–Unna–Taenzer and Orcerin staining reveals marked decrease in elastic fibers. Inflammatory infiltrate is scarce, and sometimes there may be mild perivascular lymphohistiocytic infiltrate. Subcutaneous tissue may show similar changes, but aponeurosis and muscle are usually unaffected.
Data from synovial biopsy are only available from few cases., There is mild-to-moderate synovial cell hyperplasia, with a morphologically normal lining cell layer. Within the synovium, a marked proliferation of fibroblasts in a matrix of vascular granulation tissue is observed without much inflammatory infiltrate. These proliferating cells exhibit the ultrastructural features of myofibroblasts such as indented nuclei, intracytoplasmic vesicles containing collagen fibers, linear arrays of filaments, and well-developed and cystic rough endoplasmic reticulum.
| Immunohistochemistry|| |
Immunohistochemical study of the fibroblast-like cells or spindle cells revealed that they were positive for nuclear and cytoplasmic b-catenin, anti-SMA, HHF35, and anti-calponin antibodies suggesting myofibroblastic differentiation. They are usually negative for most histiocytic markers such as CD1a, CD34, CD68, CD163, factor XIIIa, or S100 proteins.,,
| Radiology|| |
Radiography results are usually normal in the initial stages, but erosions and demineralization may occur as the disease progress. Accordingly, X-ray of hand and feet may be normal in initial stage whereas magnetic resonance imaging (MRI) may demonstrate early synovitis, tenosynovitis as well as early erosions. With progress of the disease, X-ray can demonstrate demineralization, joint space narrowing, and/or erosive changes.
In an interesting observation by Rety et al., two-third of X-rays done within first 4 months of disease onset were normal whereas rest showed only demineralization or soft tissue swelling. In most patients, destructive arthropathy of the hand developed 1 year after the onset of joint symptoms.
| Differential Diagnosis|| |
Clinically, FR has to be distinguished from other causes of dermoarthopathies that present with skin nodules and polyarthritis or polyarthralgia [Table 1]. In adults, it has to be differentiated from multicentric reticulohistiocytosis (MRH), rheumatoid arthritis (RA), progressive nodular fibrosis (PNF), and nodular scleroderma, whereas, in children, this can mimic juvenile hyaline fibromatosis (JHF).
MRH is the closest differential diagnosis of FR. Early onset erosive arthritis, mucosal involvement, and typical periungual distribution of skin nodules (coral bead appearance) suggest a diagnosis of MRH. Histopathology shows lipid-laden histiocytes and multinucleated giant cells with ground-glass cytoplasm in MRH in contrast to fibroblastic proliferation in FR.
RA when associated with rheumatoid nodules or methotrexate (MTX) nodulosis may be confused with FR. However, sparing of distal interphalangeal (DIP), typical location of rheumatoid nodules on extensor surfaces, and characteristic deformities in RA can distinguish it clinically from FR. Further positive serology (RF and anti-cyclic citrullinated peptide antibody) and elevated erythrocyte sedimentation rate and C-reactive protein favor a diagnosis of RA. Histologically, RA nodules show a shell of fibrous tissue surrounding a center of fibrinoid necrosis and intervening cellular palisade.
PNF  is another condition only presenting as cutaneous nodules, and there is no joint involvement. Skin nodules are not restricted to para-articular areas, and biopsy shows nodular proliferation of plump fibroblasts in the dermis together with thickened collagen bundles.
Nodular scleroderma  is a variant of scleroderma, which may be observed in the context of both, localized sclerosis (i.e., morphea) and systemic sclerosis. Patient usually presents with skin nodules over neck, back, and abdomen. This may be associated with other features of scleroderma such as Raynaud's, sclerodactyly, telangiectasia, polyarthralgia, or erosive arthritis involving DIPs. Skin nodules have a distinct histology, with hyalinized thickened collagen bundles, tightly bound eccrine glands, and lack of fibroblastic proliferation.
JHF  is the main differential diagnosis in children and is a rare autosomal recessive disease due to germline mutations in the capillary morphogenesis gene-2. Children with JHF also present joint contractures, bone erosion, and cutaneous nodules, which may mimic FR. Onset in infancy and early childhood, location of the skin lesions on the trunk, gingival hypertrophy, and lack of sclerodactyly favor JHF. Histopathology shows a characteristic deposition of an amorphous Periodic acid–Schiff-positive hyaline substance besides fibroblast and myofibroblast proliferation.
| Treatment|| |
Early diagnosis and treatment of FR is crucial to avoid permanent joint deformity and disability. Many anti-inflammatory and disease-modifying antirheumatic drugs (DMARDs) such as prednisone, colchicine, interferon alpha, penicillamine, MTX, hydroxychloroquine, acetylsalicylate, and nonsteroidal anti-inflammatory drugs, infliximab  have been tried in the past having variable results. As inflammatory component is much less than fibroblastic component in histopathology, improvement in joint symptoms with these agents is partial and often poor. In spite of treatment, rheumatologic features may progress to disabling condition with flexion contractures. Cutaneous nodules tend to improve faster, but it is uncertain whether this is related to the treatment, as spontaneous remission is known.
MTX causes a dose-dependent inhibition of the proliferation of cultured human synovial fibroblasts  and prevents the development of synovial fibrosis in RA. It has both antiproliferative and apoptosis-inducing effects. Low-dose oral MTX 10 mg/week was first used to treat FR in 1996 with good clinical response. It was highly effective in reducing the symptoms of joint pain, morning stiffness, and synovitis. Skin nodules completely disappeared within 2 months of treatment. Subsequently, it was tried in many patients with dose range varies from 10 to 25 mg/week and had a variable clinical response. We suggest that this difference may be related to different dosing schedules and FR may need a little higher dose of MTX than inflammatory arthritis like RA.
Interferon-alfa has been shown to reduce fibroblasts and myofibroblasts in hypertrophic scars  and likely has similar effects on fibroblasts in FR. There are case reports of effectiveness of interferon alpha in FR  Although the cutaneous nodule resolved, joint symptoms persisted. This may be related to differential antiproliferative effect of interferon-alfa on dermal fibroblast (more sensitive) than synovial fibroblast (resistant). One case report of effectiveness of infliximab  in FR suggests TNF-alpha having a pathogenic role in changing fibroblast function, and this has to prove in future studies.
As functional disability with flexion contractures remains the main long-term morbidity, role of physical therapy is crucial in maintaining joint function. One report suggests dramatic improvement with intensive physical therapy (3 times/week) without any use of pharmacological treatment. After a 2-year follow-up with weekly regular physical therapy, pain subsided, the functional impairment continuously improved, and some delicacy in the fingers movements was recovered. Follow-up MRI did not reveal any erosion or significant synovitis.
| Conclusion|| |
FR is a rarely reported condition and remains unfamiliar to most physicians. FR should be suspected and included in differential diagnosis of any patient presented with symmetrical polyarthritis, para-articular skin nodules, and flexion contracture of fingers and toes. Histopathological and immunohistochemical study of skin nodules showing fibroblastic proliferation with a decrease in elastic fibers is diagnostic of the condition. Hence, regular physical therapy with the judicious use of DMARDs and anti-inflammatory agents should be offered to all patients of FR with joint symptoms. Cutaneous nodules may resolve spontaneously.
More insight regarding origin and pathogenesis of this condition is needed to identify additional targeted therapies. Increase awareness regarding this condition is needed among both clinicians and pathologists for early diagnosis and treatment.
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Conflicts of interest
There are no conflicts of interest.
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